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Drug-induced liver injury (DILI) is one of the most frequently adverse reactions in clinical drug use, usually caused by drugs or herbal compounds. Compared with other populations, cancer patients are more prone to abnormal liver function due to primary or secondary liver malignant tumor, radiation-induced liver injury and other reasons, making potential adverse reactions from liver damage caused by anticancer drugs of particular concernduring clinical treatment process. In recent years, the application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has changed the treatment status of a series of solid malignant tumors. Unfortunately, the increasing incidence of hepatotoxicitylimits the clinical application of EGFR-TKIs. The mechanisms of liver injury caused by EGFR-TKIs were complex. Despite more than a decade of research, other than direct damage to hepatocytes caused by inhibition of cellular DNA synthesis and resulting in hepatocyte necrosis, the rest of the specific mechanisms remain unclear, and few effective solutions are available. This review focuses on the clinical feature, incidence rates and the recent advances on the discovery of mechanism of hepatotoxicity in EGFR-TKIs, as well as rechallenge and therapeutic strategies underlying hepatotoxicity of EGFR-TKIs.
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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and it carries a poor prognosis. Clarifying the pathologic mechanisms of this disease will be beneficial for the diagnosis and treatment of HCC. LncRNA MEG8 is involved in several tumors but its role in HCC progression remains unknown. This study was designed to explore the role and regulatory mechanisms of MEG8 in HCC progression. MTT, EdU, wound-healing, and transwell assays were employed to analyze the proliferation, migration, and invasion of HCC cells. A luciferase assay was utilized to confirm the predicted binding site. RNA immunoprecipitation and co-immunoprecipitation were employed to verify the binding between MEG8 and miR-367-3p as well as 14-3-3ζ and TGFßR1. Real-time PCR and western blot were employed to detect the expression of interesting genes. Results revealed that MEG8 was increased in HCC tissues and cells, and was correlated with the poor prognosis of HCC patients. Inhibiting MEG8 significantly repressed the HCC cells' ability to proliferate, migrate, and invade. Moreover, MEG8 sponged miR-367-3p to upregulate 14-3-3ζ, the binding of which suppressed TGFßR1 degradation, thereby enhancing TGFß signaling. In conclusion, this work exposed a novel role and regulatory mechanism of MEG8 in HCC and provided new insight into the treatment of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , RNA Longo não Codificante , Proteínas 14-3-3/genética , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Receptor do Fator de Crescimento Transformador beta Tipo IRESUMO
BACKGROUND: Radiotherapy is one of the main treatments for pancreatic cancer, but radiation resistance limits its clinical application. As a result, novel therapeutic agents to improve radiosensitivity are urgently needed. This study aimed to investigate the effect of Ibr-7 (a derivative of ibrutinib) on the radiosensitivity of human pancreatic cancer cells. METHODS: The effect of Ibr-7 on pancreatic cancer cell proliferation was detected by CCK-8 assays. Radiosensitivity was assessed by clonogenic formation assays. Cell cycle and cell apoptosis were analysed by flow cytometry. DNA damage was evaluated by immunofluorescence analysis. The expression levels of PARP, Cleaved caspase 3, p-EGFR and EGFR were determined by western blot. RESULTS: Ibr-7 showed an anti-proliferative effect on PANC-1 and Capan2 cells in a dose- and time-dependent manner. Ibr-7 (2 µmol/L) enhanced the effect of radiation on PANC-1 and Capan2 cells. Further findings showed that this combination enhanced G2/M phase arrest and increased cell apoptosis. Additional molecular mechanism studies revealed that the expression of p-EGFR was decreased by Ibr-7 alone or in combination with radiation. Overexpression of p-EGFR reversed the cell apoptosis induced by Ibr-7 combined with radiation. Moreover, the expression of γ-H2AX was significantly decreased in the Ibr-7 plus radiation group. CONCLUSIONS: Our study indicated the potential application of Ibr-7 as a highly effective radiosensitizer for the treatment of pancreatic cancer cells.
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OBJECTIVE: To construct the expression vector pLCK-CD69-IRES-EGFP that contains mouse cell surface activation protein CD69 and enhanced green fluorescent protein(EGFP),and to generate CD69 transgenic mice based on this vector. METHODS: First, RNA was extracted from mouse lung tissue and cDNA was synthesized via reverse transcription. PCR primer was designed through the PubMed searching, then mouse CD69 DNA fragment was amplified with PCR. Second, this DNA fragment was subcloned to the pInsulater-LCK-IRES-EGFP plasmid and constructed the transgenic vector after the verification of nucleotide sequence. Third, the expression vector was then transfected into 293 T cells and its expression in 293 T cells was observed under fluorescence microscope. Last, microinjection was performed to transfer the expression vector pLCK-CD69-IRES-EGFP into fertilized eggs, which were implanted into pseudo-pregnant recipient mice. After birth the tail samples of the pups were obtained for the purpose of genotyping to determine the transgenic founders. Fluorescence microscope and flow cytometer were used to measure the expression of CD69 on cells. RESULTS: The construction of the expression vector pLCK-CD69-IRES-EGFP was verified by enzyme digestion and DNA sequencing. The transfected 293 T cell showed expression of the protein under fluorescence microscope. Identification of PCR for the tail tissue of the pups confirmed the present of CD69 transgene and resting lymphocytes demonstrated the expression of CD69. CONCLUSION: The construction of expression vector pLCK-CD69-IRES-EGFP and generation of CD69 transgenic mice have been successfully processed, which lays a foundation of the solid pattern studies in inflammatory diseases.
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Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/genética , Vetores Genéticos , Lectinas Tipo C/genética , Camundongos Transgênicos , Animais , DNA Complementar , Genótipo , Proteínas de Fluorescência Verde/genética , Camundongos , Plasmídeos , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , TransfecçãoRESUMO
Ibrutinib is the first-in-class Bruton tyrosine kinase (BTK) inhibitor that has revolutionized the treatment of B cell malignancies. Unfortunately, increased incidences of cardiotoxicity have limited its use. Despite over a decade of research, the biological mechanisms underlying ibrutinib cardiotoxicity remain unclear. In this review, we discuss the pharmacological properties of ibrutinib, the incidence and mechanisms of ibrutinib-induced cardiotoxicity, and practical management to prevent and treat this condition. We also synopsize and discuss the cardiovascular adverse effects related to other more selective BTK inhibitors, which may guide the selection of appropriate BTK inhibitors.
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Adenina , Tirosina Quinase da Agamaglobulinemia , Cardiotoxicidade , Leucemia Linfocítica Crônica de Células B , Piperidinas , Inibidores de Proteínas Quinases , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Cardiotoxicidade/etiologia , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Macrophages are immune cells with high heterogeneity and plasticity. M2 polarization is one extreme of the well-established phenotypes of macrophage polarization, and involves in diverse biological processes. The polarization process is initiated at the command of numerous components. Long non-coding RNAs (lncRNAs) are RNAs longer than 200 nucleotides with limited protein-coding capacity. Recent studies have revealed a newly found subset of lncRNAs engaged in the M2 polarization and their potent and multifunctional roles in developing diseases. By interfering with specific signaling pathways and altering the active mode, acting as the sponges of microRNAs or decoys of transcription factors, lncRNAs prompted macrophages to an M2 phenotype. Further, lncRNAs can bind to the genome to regulate the chromatin dynamics or work as a platform for protein complexes tether. Exosomal lncRNAs can also orchestrate the polarization in a paracrine way. To make it easier to interpret the roles of lncRNAs in the M2 polarization, we review the reported lncRNAs according to the underlying mechanisms. Moreover, we discuss the possibilities of targeting macrophages' M2 polarization using the oligonucleotides drugs or clustered regularly interspaced palindromic repeats (CRISPR) technologies to provoke wisdom on the therapeutic strategies.
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Cromatina/genética , Ativação de Macrófagos/genética , Macrófagos/metabolismo , RNA Longo não Codificante/genética , HumanosRESUMO
Radiotherapy is an effective treatment for pancreatic cancer. However, radio-resistance often resulted in poor prognostic. Ibrutinib is an orally small molecule drug in B cell malignancies. Here, we investigated for the first time the effect of ibrutinib on radio-sensitivity of human pancreatic cancer cells in vitro and the potential mechanism involved in it. Human BXPC3 and Capan2 cell lines were treated with ibrutinib, and cell viability was conducted with CCK-8 assay. Cell clone formation was observed after treated with ibrutinib and (or) radiation by clone formation assay. The cell cycle and cell apoptosis were measured by flow cytometry. Protein levels was analyzed by western blot. The results revealed that ibrutinib inhibited the proliferation of pancreatic cancer cells. Ibrutinib enhanced the effect of radiation with a sensitization enhancement ratio (SER) of 1.34, 1.68 in BXPC3 and Capan2 cells respectively. Ibrutinib combined with radiation induced G2/M arrest and cell apoptosis. Further investigations revealed that ibrutinib decreased the phosphorylation of EGFR, then reversed the upregulation of p-AKT and downstream genes by radiation. In conclusion, these results suggested that ibrutinib might be an excellent radiosensitizer in pancreatic cancer.
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Adenina/análogos & derivados , Neoplasias Pancreáticas/radioterapia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Adenina/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Receptores ErbB/genética , Receptores ErbB/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Humanos , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosforilação , Transdução de SinaisRESUMO
INTRODUCTION: Kelch-like ECH associated protein 1/Nuclear factor erythroid 2-like factor 2 (Keap1-Nrf2) signaling plays a pivotal role in response to oxidative stress in lung cancer. Mutations in KEAP1/NFE2L2 genes always cause persistent Nrf2 activation in lung cancer cells that confer therapeutic resistance and aggressive tumorigenic activity, dictating either poor prognosis or short duration of response to chemotherapy in clinical observations. Areas covered: We provide a review of the mechanisms underlying the regulation of Keap1-Nrf2 at different stages, including genetic mutations, epigenetic modifications, translational/post-translational alterations, and protein-protein interactions. Based on the current knowledge, we discuss the possibilities of intervening Keap1-Nrf2 in lung adenocarcinoma as a therapeutic target. Expert opinion: It is prevalently conceived that Keap1-Nrf2 signaling plays different roles at diverse stages of cancer. Although various Nrf2 or Keap1 inhibitors have been reported during the last decades, none of these inhibitors are currently under clinical studies or in clinical applications, suggesting that sole inhibition of Nrf2 might not be sufficient to suppress tumor growth. On the basis of current studies, we suggest that the rational combination of Nrf2 suppression with chemical agents which cause enhanced oxidative imbalance or abnormal metabolism would be promising in the treatment of lung adenocarcinoma.
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Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Adenocarcinoma de Pulmão/patologia , Animais , Antineoplásicos/farmacologia , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/patologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de SinaisRESUMO
Methotrexate (MTX) is a folic acid antagonist and widely used for acute lymphoblastic leukemia (ALL) in children. MTX is associated with acute and chronic neurotoxicity during treatment, however the underlying mechanism is still poorly understood. In this study we investigate whether MTX is neurovirulent to astrocytes in the Central Nervous System (CNS) of adolescent mice. We demonstrated that MTX induced severe cytotoxicity in C6 astrocyte-like cell line and rat primary cultures of astrocytes in a dose-dependent manner. Moreover, GFAP-labeled astrocyte cells significantly decreased in the mouse spinal cord and brain. Furthermore, protein levels of PARP and pro-Caspase-3 were reduced by MTX, indicating MTX-induced apoptosis leads to the astrocytes loss. Notably, overexpression of dihydrofolate reductase (DHFR) or exogenous addition of folate markedly reversed the astrocytes toxicity induced by MTX through activating folate metabolism pathway. Taken together, our study provides evidence for neurotoxic effect of MTX-induced astrocytes apoptosis both in vitro and in vivo with disruption of folate metabolism, and additional supplement of folate may provide novel approaches for alleviating the astrocytes toxicity induced by MTX in the clinic.
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Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Ácido Fólico/metabolismo , Metotrexato/toxicidade , Animais , Astrócitos/citologia , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sistema Nervoso Central/metabolismo , Relação Dose-Resposta a Droga , Antagonistas do Ácido Fólico/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Ratos , Tetra-Hidrofolato Desidrogenase/genética , Tetra-Hidrofolato Desidrogenase/metabolismoRESUMO
Bruceine D (BD) is the quassinoids isolated from the traditional Chinese herbal medicine Brucea javanica's fruit, which exhibits anti-cancer activity. Here, we demonstrated that BD inhibited human non-small cell lung cancer (NSCLC) cell lines in vitro that were attributed to the induction of cell apoptosis. Human NSCLC H460 and A549 cell lines were treated with BD, and cell viability was conducted with CCK-8 assay. Cell clone formation was observed by clone formation assay. Cell apoptosis was measured using DAPI staining and flow cytometry. Protein levels was analyzed by western blot. The results showed BD inhibited the cell viability of H460 and A549 cells in a dose-dependent manner with IC50 values of 0.5 and 0.6⯵mol/L, respectively, at 48â¯h of treatment. Treatment with BD (0.125-1.0⯵mol/L) dose-dependently promoted chromatin condensation, Annexin V-positive cell population and caspase-dependent apoptosis in H460 and A549 cells. Mechanistically, BD stimulated the phosphorylation of JNK. Furthermore, the anti-cancer effects of BD were alleviated effectively by a specific JNK inhibitor SP600125 in NSCLC cells. In conclusion, the results demonstrated that BD exerted anti-cancer activity against NSCLC cells through JNK activation, which suggests its potent usefulness for prevention and treatment of NSCLC.
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Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quassinas/farmacologia , Células A549 , Antineoplásicos Fitogênicos/farmacologia , Brucea/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Fosforilação/efeitos dos fármacosRESUMO
Glioma is one of the most lethal malignancies and molecular regulators driving gliomagenesis are incompletely understood. Although temozolomide (TMZ) has been applied for malignant gliomas as a canonical chemotherapy, the treatment of glioma still remains limited due to frequently developed resistance to TMZ. Therefore, promising strategies that sensitize glioma cells to temozolomide are overwhelming to develop. Here we found that the expression of dihydrofolate reductase (DHFR) and thymidylate synthetase (TYMS), which played an essential role in folate metabolism and several types of tumors, were up-regulated in both human glioma tissues and cell lines, and overexpression of DHFR/TYMS promoted the proliferation of glioma cells. Notably, inhibition of DHFR/TYMS by pemetrexed exhibited synergistic anti-glioma activity with TMZ in both cell lines and U251 xenografts, which suggested potential combined chemotherapy for glioma. Mechanistically, the synergistic effect of inhibition of DHFR/TYMS with TMZ was due to activated AMPK and subsequently suppressed mTOR signaling pathway. Taken together, these findings identify an uncharacterized role of DHFR/TYMS in glioma growth and TMZ sensitivity mediated by AMPK-mTOR signal pathway, and provide a prospective approach for improving the anti-tumor activity of TMZ in glioma.
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Glioma/patologia , Temozolomida/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Timidilato Sintase/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Antagonistas do Ácido Fólico/farmacologia , Glioma/tratamento farmacológico , Glioma/enzimologia , Humanos , Camundongos , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Timidilato Sintase/antagonistas & inibidores , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tumor imaging tools with high specificity and sensitivity are needed to aid the boundary recognition in solid tumor diagnosis and surgical resection. In this study, we developed a near infra-red (NIR) probe (P6) for in vitro/in vivo tumor imaging on the basis of the dual strategy of cancer cell targeting and stimulus-dependent activation. The selective imaging capacity towards cancer cells of P6 was thoroughly investigated, and the potential mechanisms of endocytosis were preliminary explored. Methods: GSH-activated biotin labelled NIR probe (P6) was designed, synthesized and characterized. The GSH responsive properties were systematically illustrated through UV-vis, fluorescent tests and LC-MS analysis. In vitro fluorescent imaging of probe P6 was collected in various living cancer cell lines (i.e. SW480, HGC-27, H460, BxPC-3, KHOS) and normal cell lines (i.e. BEAS-2B, HLF-1, THP1) under confocal laser scanning microscopy. Probe P6 was further applied to image primary human cancer cells which were freshly isolated from the peritoneal carcinoma and rectal cancer patients. Serial sections of human tumor tissues were collected and sent for H&E (hematoxylin-eosin) staining and P6 imaging. Live fluorescent and photoacoustic imaging were used to investigate the in vivo imaging of P6 in both tumor and normal tissues in HGC-27 and KHOS xenograft model. Results: Probe P6 could be recognized and transported into cancer cells by tumor specific biotin receptors and efficiently be triggered by GSH to release fluorophore 4. In fact, the cellular uptake of P6 could be partially blocked by the addition of free biotin. Furthermore, probe P6 could image various cancer cell lines, as well as primary cancer cells, exhibiting a ten-fold increase in fluorescence intensity over normal cells. In freshly dissected cancer tissues, P6 fluorescent imaging distinguished the cancerous area under confocal laser scanning microscopy, which was exact the same area as indicated by H&E staining. We also found that P6 exhibited superior selectivity against cancer tissues by local injection. Conclusion: In this study, we developed a dual-modal NIR probe P6 with enhanced cellular uptake into cancer cells and environmental stimulus triggered fluorescence. Our strategy provided a novel insight into the development of imaging tools that could be potentially used for fluorescent image-guided cancer boundary recognition and possibly cancer diagnosis.
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Biotina/metabolismo , Carcinoma/diagnóstico por imagem , Glutationa/metabolismo , Sondas Moleculares/síntese química , Sondas Moleculares/metabolismo , Imagem Óptica/métodos , Osteossarcoma/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Endocitose , Humanos , Modelos Biológicos , Transplante de Neoplasias , Técnicas Fotoacústicas/métodos , Transplante HeterólogoRESUMO
As patients with nonsmall cell lung cancer (NSCLC) and wildtype epidermal growth factor receptor (EGFR) are resistant to treatment with erlotinib or gefitinib, potential chemosensitizers are required to potentiate wildtype EGFR NSCLC cells to erlotinib/gefitinib treatment. The present study reported that shikonin could sensitize the anticancer activity of erlotinib/gefitinib in wildtype EGFR NSCLC cells. Furthermore, shikonin could potentiate mitochondrialmediated apoptosis induced by erlotinib/gefitinib in wildtype EGFR NSCLC cells. In addition, the present study demonstrated that shikonin could induce apoptosis by activating reactive oxygen species (ROS)mediated endoplasmic reticulum (ER) stress, and that erlotinib/gefitinib may also induce ER stress in wildtype EGFR NSCLC cells; however, shikonin plus erlotinib/gefitinib was more effective in activating ER stress than either agent alone. This indicated that ROSmediated ER stress may be associated with enhanced mitochondrial apoptosis induced by shikonin plus erlotinib/gefitinib. In addition, shikonin may promote the transition of cytoprotective ER stressinducing EGFRtyrosine kinase inhibitor tolerance to apoptosispromoting ER stress. Furthermore, shikonin may enhance the antiNSCLC activity of erlotinib/gefitinib in vivo. The data of the present study indicated that shikonin may be a potential sensitizer to enhance the anticancer efficacy of erlotinib/gefitinib in wildtype EGFR NSCLC cells resistant to erlotinib/gefitinib treatment.
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Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/farmacologia , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Naftoquinonas/farmacologia , Células A549 , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Lithospermum/química , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Nus , Naftoquinonas/química , Inibidores de Proteínas Quinases/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Folate, an essential micronutrient, is a critical cofactor in one-carbon metabolism for many cellular pathways including DNA synthesis, metabolism and maintenance. Folate deficiency has been associated with an increased risk of neurological disease, cancer and cognitive dysfunction. Dihydrofolate reductase (DHFR) is a key enzyme to regulate folate metabolism, however folate/DHFR activity in oligodendrocyte development has not been fully understood. Here we show that folate enhances oligodendrocyte maturation both in vitro and in vivo, which is accompanied with upregulation of oligodendrocyte-specific DHFR expression. On the other hand, pharmacological inhibition of DHFR by methotrexate (MTX) causes severe defects in oligodendrocyte survival and differentiation, which could be reversed by folate intake. We further demonstrate that folate activates a metabolic regulator AMPKα to promote oligodendrocyte survival and differentiation. Moreover, activation of AMPKα partially rescues oligodendrocyte defects caused by DHFR-inhibition both in vitro and in vivo. Taken together, these findings identify a previously uncharacterized role of folate/DHFR/AMPKα axis in regulating oligodendrocyte survival and myelination during CNS development.
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Adenilato Quinase/metabolismo , Diferenciação Celular , Ácido Fólico/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Animais , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Antagonistas do Ácido Fólico/farmacologia , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Oligodendroglia/enzimologia , Nervo Óptico/patologia , Nervo Óptico/ultraestrutura , Fosforilação/efeitos dos fármacos , Medula Espinal/patologia , Medula Espinal/ultraestrutura , Tetra-Hidrofolato Desidrogenase/metabolismoRESUMO
Several studies have showed the anti-cancer efficacy of 5-FU (5-fluorouracil) on pediatric tumors. Although the delayed demyelination induced by 5-FU in adult patients has been reported, the effect of 5-FU on oligodendrocyte myelination in adolescence is still unknown. Here, we demonstrate that systemic administration with 5-FU leads to immediate demyelination in the central nervous system (CNS) of adolescent mice, which is mainly attributed to the death of OLs. Gene-chip microarray transcriptome analysis identifies that oligodendrocyte-specific factor TCF7L2 may be a toxic target of 5-FU-impaired myelination. 5-FU-decreased TCF7L2 results in disruption of the interaction between TCF7L2 and HDAC1/2. Inhibition of crucial myelination-promoting factors by 5-FU is more significantly antagonized by co-transfection of TCF7L2, HDAC1 and HDAC2 than TCF7L2 alone. Our findings reveal that 5-FU could acutely induce the severe myelin degeneration in adolescence and disruption of TCF7L2/HDAC1/HDAC2 complex is at least partially involved in 5-FU-induced demyelination.
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Antimetabólitos Antineoplásicos/toxicidade , Encéfalo/efeitos dos fármacos , Doenças Desmielinizantes/induzido quimicamente , Fluoruracila/toxicidade , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Oligodendroglia/efeitos dos fármacos , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Fatores Etários , Animais , Encéfalo/enzimologia , Encéfalo/patologia , Morte Celular/efeitos dos fármacos , Células Cultivadas , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Perfilação da Expressão Gênica/métodos , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Camundongos Endogâmicos C57BL , Complexos Multiproteicos , Oligodendroglia/enzimologia , Oligodendroglia/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , TransfecçãoRESUMO
BACKGROUND: Accurate data on coverage of key maternal, newborn, and child health (MNCH) interventions are crucial for monitoring progress toward the Millennium Development Goals 4 and 5. Coverage estimates are primarily obtained from routine population surveys through self-reporting, the validity of which is not well understood. We aimed to examine the validity of the coverage of selected MNCH interventions in Gongcheng County, China. METHOD AND FINDINGS: We conducted a validation study by comparing women's self-reported coverage of MNCH interventions relating to antenatal and postnatal care, mode of delivery, and child vaccinations in a community survey with their paper- and electronic-based health care records, treating the health care records as the reference standard. Of 936 women recruited, 914 (97.6%) completed the survey. Results show that self-reported coverage of these interventions had moderate to high sensitivity (0.57 [95% confidence interval (CI): 0.50-0.63] to 0.99 [95% CI: 0.98-1.00]) and low to high specificity (0 to 0.83 [95% CI: 0.80-0.86]). Despite varying overall validity, with the area under the receiver operating characteristic curve (AUC) ranging between 0.49 [95% CI: 0.39-0.57] and 0.90 [95% CI: 0.88-0.92], bias in the coverage estimates at the population level was small to moderate, with the test to actual positive (TAP) ratio ranging between 0.8 and 1.5 for 24 of the 28 indicators examined. Our ability to accurately estimate validity was affected by several caveats associated with the reference standard. Caution should be exercised when generalizing the results to other settings. CONCLUSIONS: The overall validity of self-reported coverage was moderate across selected MNCH indicators. However, at the population level, self-reported coverage appears to have small to moderate degree of bias. Accuracy of the coverage was particularly high for indicators with high recorded coverage or low recorded coverage but high specificity. The study provides insights into the accuracy of self-reports based on a population survey in low- and middle-income countries. Similar studies applying an improved reference standard are warranted in the future.
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Serviços de Saúde da Criança/provisão & distribuição , Serviços de Saúde Materna/provisão & distribuição , Prontuários Médicos , População Rural/estatística & dados numéricos , Autorrelato , Adolescente , Adulto , China , Feminino , Humanos , Recém-Nascido , Pessoa de Meia-Idade , Gravidez , Adulto JovemRESUMO
This letter describes the construction of conformationally constrained quinazoline analogues. Structure-activity relationship studies led to the identification of the lead compound 9n . Compound 9n exhibits effective in vitro activity against A431(WT,overexpression) and H1975([L858R/T790M]) cancer cell lines but is significantly less effective against EGFR negative cancer cell lines (SW620, A549, and K562). Compound 9n was also assessed for potency in enzymatic assays and in vivo antitumor studies. The results indicated that 9n is a potent kinase inhibitor against both wild-type and T790M mutant EGFR kinase. Meanwhile, an oral administration of 9n at a dose of 200 mg/kg produced a considerable antitumor effect in a A431 xenograft model, as compared to gefitinib. A preliminary pharmacokinetic study of 9n also indicates it has good pharmacokinetic properties, and therefore, it is a good starting point for further development.