RESUMEN
OBJECTIVE: Therapy-induced tumour microenvironment (TME) remodelling poses a major hurdle for cancer cure. As the majority of patients with hepatocellular carcinoma (HCC) exhibits primary or acquired resistance to antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) therapies, we aimed to investigate the mechanisms underlying tumour adaptation to immune-checkpoint targeting. DESIGN: Two immunotherapy-resistant HCC models were generated by serial orthotopic implantation of HCC cells through anti-PD-L1-treated syngeneic, immunocompetent mice and interrogated by single-cell RNA sequencing (scRNA-seq), genomic and immune profiling. Key signalling pathway was investigated by lentiviral-mediated knockdown and pharmacological inhibition, and further verified by scRNA-seq analysis of HCC tumour biopsies from a phase II trial of pembrolizumab (NCT03419481). RESULTS: Anti-PD-L1-resistant tumours grew >10-fold larger than parental tumours in immunocompetent but not immunocompromised mice without overt genetic changes, which were accompanied by intratumoral accumulation of myeloid-derived suppressor cells (MDSC), cytotoxic to exhausted CD8+ T cell conversion and exclusion. Mechanistically, tumour cell-intrinsic upregulation of peroxisome proliferator-activated receptor-gamma (PPARγ) transcriptionally activated vascular endothelial growth factor-A (VEGF-A) production to drive MDSC expansion and CD8+ T cell dysfunction. A selective PPARγ antagonist triggered an immune suppressive-to-stimulatory TME conversion and resensitised tumours to anti-PD-L1 therapy in orthotopic and spontaneous HCC models. Importantly, 40% (6/15) of patients with HCC resistant to pembrolizumab exhibited tumorous PPARγ induction. Moreover, higher baseline PPARγ expression was associated with poorer survival of anti-PD-(L)1-treated patients in multiple cancer types. CONCLUSION: We uncover an adaptive transcriptional programme by which tumour cells evade immune-checkpoint targeting via PPARγ/VEGF-A-mediated TME immunosuppression, thus providing a strategy for counteracting immunotherapeutic resistance in HCC.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Carcinoma Hepatocelular/patología , Factor A de Crecimiento Endotelial Vascular , Neoplasias Hepáticas/patología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , PPAR gamma , Microambiente Tumoral , Antígeno B7-H1RESUMEN
Weighted gene co-expression network analysis (WGCNA) identified a cell-cycle module that is associated with poor prognosis and aggressiveness of glioma. One of the core members, Regulator of chromatin condensation 2 (RCC2) is a component of the chromosome passenger complex. Accumulating evidence suggests that RCC2 plays a vital role in the mitotic process and that abnormal RCC2 expression is involved in cancer development. Gene silencing experiments show that RCC2 is required for glioma cell proliferation and migration. RNA-Sequencing analysis reveals a dual role of RCC2 in both the cell cycle and metabolism. Specifically, RCC2 regulates G2/M progression via CDC2 phosphorylation at Tyrosine 15. Metabolomic analysis identifies a role for RCC2 in promoting the glycolysis and pentose phosphate pathway. RCC2 exerts effects on metabolism by stabilizing the transcription factor BACH1 at its C-terminus leading to the transcriptional upregulation of hexokinase 2 (HK2). These findings elucidate a novel PTEN/RCC2/BACH1/HK2 signaling axis that drives glioma progression through the dual regulation of mitotic cell cycle and glycolytic events.
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Glioma , Hexoquinasa , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Línea Celular Tumoral , Proliferación Celular , Cromatina , Proteínas Cromosómicas no Histona , Cromosomas/metabolismo , Glioma/genética , Glucosa , Glucólisis , Factores de Intercambio de Guanina Nucleótido , Hexoquinasa/genética , Humanos , ARN/metabolismo , Factores de Transcripción/genética , Tirosina/metabolismo , Regulación hacia ArribaRESUMEN
Glioblastoma multiforme (GBM) is the most prevalent type and lethal form of primary malignant brain tumor, accounting for about 40-50% of intracranial tumors and without effective treatments now. Cell reprogramming is one of the emerging treatment approaches for GBM, which can reprogram glioblastomas into non-tumor cells to achieve therapeutic effects. However, anti-GBM drugs through reprogramming can only provide limited symptom relief, and cannot completely cure GBM. Here we showed that PT109, a novel multi-kinase inhibitor, suppressed GBM's proliferation, colony formation, migration and reprogramed GBM into oligodendrocytes. Analysis of quantitative proteomics data after PT109 administration of human GBM cells showed significant influence of energy metabolism, cell cycle, and immune system processes of GBM-associated protein. Metabolomics analysis showed that PT109 improved the aerobic respiration process in glioma cells. Meanwhile, we found that PT109 could significantly increase the ratio of Pyruvate kinase M1/2 (PKM1/2) by reducing the level of polypyrimidine tract-binding protein 1 (PTBP1). Altogether, this work developed a novel anti-GBM small molecule PT109, which reprogramed GBM into oligodendrocytes and changed the metabolic pattern of GBM through the PTBP1/PKM1/2 pathway, providing a new strategy for the development of anti-glioma drugs.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular , Reprogramación Celular , Glioblastoma/patología , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Humanos , Compuestos Organoplatinos , Proteína de Unión al Tracto de Polipirimidina/genética , Proteína de Unión al Tracto de Polipirimidina/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) is a major cancer burden worldwide with increasing incidence in many developed countries. Super-enhancers (SEs) drive gene expressions required for cell type-specificity and tumor cell identity. However, their roles in HCC remain unclear because of data scarcity from primary tumors. Herein, chromatin profiling of non-alcoholic fatty liver disease (NAFLD)-associated HCCs and matched liver tissues uncovered an average of â¼500 somatically-acquired SEs per patient. The identified SE-target genes were functionally enriched for aberrant metabolism and cancer phenotypes, especially chromatin regulators including deacetylases and Polycomb repressive complexes. Notably, all examined tumors exhibited SE activation of Sirtuin 7 (SIRT7), genome-wide promoter H3K18 deacetylation and concurrent H3K27me3, as well as tumor-suppressor gene silencing. Depletion of SIRT7 SE in hepatoma cells induced global H3K18 acetylation and reactivated key metabolic and immune regulators, leading to marked suppression of tumorigenicity in vitro and in vivo. In concordance, SIRT7 physically interacted with the methyltransferase EZH2, and they were co-expressed in primary HCCs. In summary, our integrative analysis establishes a compendium of SEs in NAFLD-associated HCCs and uncovers SIRT7-driven chromatin regulatory network as potential druggable vulnerability of this increasingly prevalent cancer.
Asunto(s)
Carcinoma Hepatocelular/genética , Elementos de Facilitación Genéticos/genética , Neoplasias Hepáticas/genética , Sirtuinas/genética , Carcinogénesis/genética , Carcinoma Hepatocelular/patología , Reprogramación Celular/genética , Epigenómica , Femenino , Silenciador del Gen , Humanos , Neoplasias Hepáticas/patología , Masculino , Sirtuinas/antagonistas & inhibidoresRESUMEN
Traditional EZH2 inhibitors are developed to suppress the enzymatic methylation activity, and they may have therapeutic limitations due to the nonenzymatic functions of EZH2 in cancer development. Here, we report proteolysis-target chimera (PROTAC)-based EZH2 degraders to target the whole EZH2 in lymphoma. Two series of EZH2 degraders were designed and synthesized to hijack E3 ligase systems containing either von Hippel-Lindau (VHL) or cereblon (CRBN), and some VHL-based compounds were able to mediate EZH2 degradation. Two best degraders, YM181 and YM281, induced robust cell viability inhibition in diffuse large B-cell lymphoma (DLBCL) and other subtypes of lymphomas, outperforming a clinically used EZH2 inhibitor EPZ6438 (tazemetostat) that was only effective against DLBCL. The EZH2 degraders displayed promising antitumor activities in lymphoma xenografts and patient-derived primary lymphoma cells. Our study demonstrates that EZH2 degraders have better therapeutic activity than EZH2 inhibitors, which may provide a potential anticancer strategy to treat lymphoma.
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Antineoplásicos/farmacología , Diseño de Fármacos , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Linfoma/tratamiento farmacológico , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Humanos , Linfoma/metabolismo , Linfoma/patología , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales Cultivadas , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismoRESUMEN
Insufficient T cell infiltration into noninflamed tumors, such as hepatocellular carcinoma (HCC), restricts the effectiveness of immune-checkpoint blockade (ICB) for a subset of patients. Epigenetic therapy provides further opportunities to rewire cancer-associated transcriptional programs, but whether and how selective epigenetic inhibition counteracts the immune-excluded phenotype remain incompletely defined. Here, we showed that pharmacological inhibition of histone deacetylase 8 (HDAC8), a histone H3 lysine 27 (H3K27)-specific isozyme overexpressed in a variety of human cancers, thwarts HCC tumorigenicity in a T cell-dependent manner. The tumor-suppressive effect of selective HDAC8 inhibition was abrogated by CD8+ T cell depletion or regulatory T cell adoptive transfer. Chromatin profiling of human HDAC8-expressing HCCs revealed genome-wide H3K27 deacetylation in 1251 silenced enhancer-target gene pairs that are enriched in metabolic and immune regulators. Mechanistically, down-regulation of HDAC8 increased global and enhancer acetylation of H3K27 to reactivate production of T cell-trafficking chemokines by HCC cells, thus relieving T cell exclusion in both immunodeficient and humanized mouse models. In an HCC preclinical model, selective HDAC8 inhibition increased tumor-infiltrating CD8+ T cells and potentiated eradication of established hepatomas by anti-PD-L1 therapy without evidence of toxicity. Mice treated with HDAC8 and PD-L1 coblockade were protected against subsequent tumor rechallenge as a result of the induction of memory T cells and remained tumor-free for greater than 15 months. Collectively, our study demonstrates that selective HDAC8 inhibition elicits effective and durable responses to ICB by co-opting adaptive immunity through enhancer reprogramming.
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Carcinoma Hepatocelular , Inhibidores de Histona Desacetilasas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Hepáticas , Animales , Linfocitos T CD8-positivos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/inmunología , Línea Celular Tumoral , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Ratones , Proteínas RepresorasRESUMEN
Alzheimer's disease (AD), which is characterized by impairment of cognitive functions, is a chronic neurodegenerative disease that mainly affects the elderly. Currently available anti-AD drugs can only offer limited symptom-relieving effects. "One-compound-Multitargeted Strategy" have been recognized as the promising way to win the war against AD. Herein we report a potential anti-AD agent PT109 with multi-functions. First, an 81-kinase screening was carried out and results showed that PT109 potently inhibited c-Jun N-terminal kinases and Serum and glucocorticoid-inducible kinase 1, which are the important signaling molecules involved in neurogenesis, neuroprotection and neuroinflammation and mildly inhibit glycogen synthase kinase-3ß as well as protein kinase C gamma, both are involved in AD pathological processes. In addition, invitro studies of immunofluorescent staining and Western blot showed that PT109 might promote the neurogenesis of C17.2 cells and induce synaptogenesis in primary cultured rat hippocampal neurons. We detected and confirmed the neuroprotective effect of PT109 in cultured HT22 cells by MTT assay, dehydrogenase assay, glutathione assay and reactive oxygen species assay. Furthermore, the results of Western blot, ELISA assay and immunofluorescent staining indicated that PT109 attenuated lipopolysaccharide-induced inflammation in BV2 cells and primary astrocytes. The results of Morris water maze and Step-through test indicated that PT109 improved the spatial learning ability in APP/PS1 mice. More importantly, the invivo pharmacokinetic parameters indicated that PT109 had better medicinal properties. Taken together, our findings suggest that PT109 may be a promising candidate for treating AD through multiple targets although further studies are ought to be conducted.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Descubrimiento de Drogas , Neurogénesis/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular , Citocinas/metabolismo , Modelos Animales de Enfermedad , Proteínas Inmediatas-Precoces/antagonistas & inhibidores , Proteínas Inmediatas-Precoces/metabolismo , Mediadores de Inflamación/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Locomoción/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Terapia Molecular Dirigida , Prueba del Laberinto Acuático de Morris/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/farmacocinética , Presenilina-1/genética , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
The cancer clinical therapy of doxorubicin (Dox) treatment is limited by its life-threatening cardiotoxic effects. Dickkopf-1 (Dkk1), the founding and best-studied member of the Dkk family, functions as an antagonist of canonical Wnt/ß-catenin. Dkk1 is considered to play a broad role in a variety of biological processes, but its effects on Dox-induced cardiomyopathy are poorly understood. Here, we found that the level of Dkk1 was significantly increased in Dox-treated groups, and this increase exacerbated Dox-induced cardiomyocyte apoptosis and mitochondrial dysfunction. Overexpressing Dkk1 aggravated Dox-induced cardiotoxicity in H9C2 cells. Similar results were detected when adding active Dkk1 protein extracellularly. Conversely, adding specific antibody blocking extracellular Dkk1 attenuated the cardiotoxic response to Dox. Adenovirus encoding Dkk1 was transduced through intramyocardial injection and exacerbated Dox-induced cardiomyocyte apoptosis, mitochondrial damage and heart injury in vivo Furthermore, Wnt/ß-catenin signaling was inhibited during Dox-induced cardiotoxicity, and the re-activation of ß-catenin prevented the effect of overexpressed Dkk1 and Dox-induced cardiotoxicity. In conclusion, these results reveal the crucial role of the Dkk1-Wnt/ß-catenin signaling axis in the process of Dox-induced cardiotoxicity and provide novel insights into the potential mechanism of cardiomyopathy caused by clinical application of Dox.
Asunto(s)
Cardiotoxicidad/etiología , Doxorrubicina/toxicidad , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Animales , Antibióticos Antineoplásicos/toxicidad , Apoptosis/fisiología , Cardiotoxicidad/genética , Cardiotoxicidad/metabolismo , Cardiotoxicidad/patología , Línea Celular , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba/efectos de los fármacos , Proteínas Wnt/antagonistas & inhibidores , Proteínas Wnt/metabolismo , beta Catenina/antagonistas & inhibidores , beta Catenina/metabolismoRESUMEN
Glioblastoma multiforme (GBM) is the most malignant type of primary brain tumor in adults and can diffusely infiltrate adjacent normal tissue. GBM is therefore rarely cured by surgery or radiation therapy. Matrix metalloproteinases (MMPs) are involved in tissue remodeling and numerous other physiological progresses. The MMPs MMP-2 and MMP-9 are associated with the invasion ability of GBM. PT93 is a novel caffeic acid amide derivative that was first synthesized in 2013. In the present study, the human GBM T98G, U87 and U251 cell lines and the normal mouse neuron HT22 cell line were used to investigate the anticancer and cytotoxic effects of PT93 in vitro. The cytotoxicity of PT93 was measured using MTT and lactate dehydrogenase assays. The anti-proliferation effect was tested using a cell colony formation assay. Gelatin zymography analysis and a scratch test were used to investigate the anti-migration mechanism of PT93. Western blot analysis was used to measure the expression of MMP-2/-9. The experimental results showed that PT93 suppressed the proliferation of T98G cells, and showed cytotoxicity effects at high concentration in T98G, U87, U251 and HT22 cell lines. Furthermore, PT93 limited the migration ability of the cells and inhibited the extracellular MMP-2 and MMP-9 activity of T98G and U251 cells. Finally, the present study confirmed that PT93 affects the level of MMP-2/-9 expression in T98G cells in a concentration-dependent manner. The present study indicates that PT93, as a novel caffeic acid amide derivative, may be used in the treatment of GBM.
RESUMEN
PURPOSE: Numerous studies have reported that glioma patients with isocitrate dehydrogenase 1(IDH1) R132H mutation are sensitive to temozolomide treatment. However, the mechanism of IDH1 mutations on the chemosensitivity of glioma remains unclear. In this study, we investigated the role and the potential mechanism of Nrf2 in IDH1 R132H-mediated drug resistance. METHODS: Wild type IDH1 (R132H-WT) and mutant IDH1 (R132H) plasmids were constructed. Stable U87 cells and U251 cells overexpressing IDH1 were generated. Phenotypic differences between IDH1-WT and IDH1 R132H overexpressing cells were evaluated using MTT, cell colony formation assay, scratch test assay and flow cytometry. Expression of IDH1 and its associated targets, nuclear factor-erythroid 2-related factor 2 (Nrf2), NAD(P)H quinine oxidoreductase 1 (NQO1), multidrug resistant protein 1 (MRP1) and p53 were analyzed. RESULTS: The IDH1 R132H overexpressing cells were more sensitive to temozolomide than WT and the control, and Nrf2 was significantly decreased in IDH1 R132H overexpressing cells. We found that knocking down Nrf2 could decrease resistance to temozolomide. The nuclear translocation of Nrf2 in IDH1 R132H overexpressing cells was lower than the WT and the control groups after temozolomide treatment. When compared with WT cells, NQO1 expression was reduced in IDH1 R132H cells, especially after temozolomide treatment. P53 was involved in the resistance mechanism of temozolomide mediated by Nrf2 and NQO1. CONCLUSIONS: Nrf2 played an important role in IDH1 R132H-mediated drug resistance. The present study provides new insight for glioma chemotherapy with temozolomide.
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Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Dacarbazina/análogos & derivados , Glioma/tratamiento farmacológico , Isocitrato Deshidrogenasa/genética , Mutación/genética , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Dacarbazina/farmacología , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Humanos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/genética , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Factor 2 Relacionado con NF-E2/genética , Transducción de Señal , Temozolomida , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Microglia and astrocytes are largely responsible for inflammatory injury in the brain of Alzheimer's disease (AD). Increasing evidence has indicated that Rho kinase (ROCK) plays an important role in the regulation of neuroinflammation. Previously, we synthesized a new chemical entity L-F001 and proved its potential inhibitory effects on ROCK and oxidative stress. Here, we investigated the anti-inflammatory effects and the molecular mechanisms of L-F001 in vitro and in vivo. L-F001 remarkably suppressed lipopolysaccharides (LPS)-elevated expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as LPS-induced production of nitric oxide (NO), reactive oxygen species, interleukin-6 (IL-6) and tumor necreactive oxygen speciesis factor-α (TNF-α) in microglial BV-2 cells and in cultured astrocytes. Furthermore, L-F001 inhibited the degradation of IκB and nuclear translocation of nuclear factor kappa B (NF-κB) p65 subunit. Moreover, L-F001 induced the upregulation of heme-oxygenase-1 (HO-1) and glutamate cysteine ligase modifier subunit (GCLM) expression, two downstream effectors of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). It was interesting that L-F001 also activated phosphatidylinositol 3-kinase (PI3K) pathway and induced M1 (CD16/32, M1 marker)/ M2 (CD206, M2 maker) transition in BV-2 cells which was significantly blocked by a PI3K inhibitor, wortmannin. Finally, L-F001 markedly attenuated the level of pro-inflammatory mediators in a murine model of systemic acute brain inflammation induced by LPS. Taken together, these results indicate that the novel multifunctional ROCK inhibitor L-F001 suppresses neuroinflammation in vitro and in vivo via NF-κB inhibition and Nrf2 activation, suggesting that L-F001 may be a promising drug candidate for treating neuroinflammation-associated CNS diseases, including AD.
Asunto(s)
Azepinas/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Sulfonamidas/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Transporte Activo de Núcleo Celular/efectos de los fármacos , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Azepinas/uso terapéutico , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Sulfonamidas/uso terapéutico , Factor de Transcripción ReIA/metabolismoRESUMEN
The microglia-mediated neuroinflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Advanced glycation end products (AGEs)/receptor for advanced glycation end products (RAGE) or Rho/Rho kinase (ROCK) are both involved in the development of non-specific inflammation. However, there are few reports about their effects on neuroinflammation. Here, we explored the mechanism of AGEs/RAGE/Rho/ROCK pathway underlying the non-specific inflammation and microglial polarization in BV2 cells. AGEs could activate ROCK pathway in a concentration-dependent manner. ROCK inhibitor fasudil and RAGE-specific blocker FPS-ZM1 significantly inhibited AGEs-mediated activation of BV2 cells and induction of reactive oxygen species (ROS). FPS-ZM1 and fasudil exerted their anti-inflammatory effects by downregulating inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), NLRP3 and nuclear translocation of nuclear factor kappa B (NF-κB) p65. In addition, AGEs induced both M1 (CD16/32, M1 marker) and M2 (CD206, M2 marker) phenotype in BV2 cells. Fasudil and FPS-ZM1 led to a decreased M1 and increased M2 phenotype. Together, these results indicate that the AGEs/RAGE/Rho/ROCK pathway in BV2 cells could intensify the non-specific inflammation of AD, which will provide novel strategies for the development of anti-AD drugs.
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Proteínas de Unión al Calcio/metabolismo , Polaridad Celular/fisiología , Productos Finales de Glicación Avanzada/metabolismo , Proteínas de Microfilamentos/metabolismo , Microglía/fisiología , FN-kappa B/metabolismo , Transducción de Señal/fisiología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Animales , Benzamidas/farmacología , Miosinas Cardíacas/metabolismo , Línea Celular Transformada , Polaridad Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Productos Finales de Glicación Avanzada/farmacología , Ratones , Microglía/clasificación , Microglía/efectos de los fármacos , Cadenas Ligeras de Miosina/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Quinasas Asociadas a rho/metabolismoRESUMEN
A series of rivastigmine-caffeic acid and rivastigmine-ferulic acid hybrids were designed, synthesized, and evaluated as multifunctional agents for Alzheimer's disease (AD) in vitro. The new compounds exerted antioxidant neuroprotective properties and good cholinesterases (ChE) inhibitory activities. Some of them also inhibited amyloid protein (Aß) aggregation. In particular, compound 5 emerged as promising drug candidates endowed with neuroprotective potential, ChE inhibitory, Aß self-aggregation inhibitory and copper chelation properties. These data suggest that compound 5 offers an attractive starting point for further lead optimization in the drug-discovery process against AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Ácidos Cumáricos/farmacología , Rivastigmina/farmacología , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Antioxidantes/química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacocinética , Ácidos Cumáricos/química , Descubrimiento de Drogas/métodos , Humanos , Técnicas In Vitro/métodos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Rivastigmina/química , Relación Estructura-ActividadRESUMEN
Neural stem cells (NSCs) are multipotent cells which are capable of self-replication and differentiation into neurons, astrocytes or oligodendrocytes in the central nervous system (CNS). NSCs are found in two main regions in the adult brain: the subgranular zone (SGZ) in the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ). The recent discovery of NSCs in the adult mammalian brain has fostered a plethora of translational and preclinical studies to investigate novel approaches for the therapy of neurodegenerative diseases. Melatonin is the major secretory product synthesized and secreted by the pineal gland and shows both a wide distribution within phylogenetically distant organisms from bacteria to humans and a great functional versatility. Recently, accumulated experimental evidence showed that melatonin plays an important role in NSCs, including its proliferation, differentiation and survival, which are modulated by many factors including MAPK/ERK signaling pathway, histone acetylation, neurotrophic factors, transcription factors, and apoptotic genes. The purpose of this review is to summarize the beneficial effects of melatonin on NSCs and further to discuss the potential usage of melatonin and its derivatives or analogues in the treatment of CNS neurodegenerative diseases.