RESUMO
The dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and/or solute carrier family 7 member 11 (SLC7A11) is believed to contribute to ferroptosis in the hearts suffered ischemia/reperfusion (I/R), but the mechanisms behind the dysregulation of them are not fully elucidated. Mucosa associated lymphoid tissue lymphoma translocation gene 1 (MALT1) can function as a paracaspase to cleave specified substrates and it is predicted to interact with Nrf2. This study aims to explore whether targeting MALT1 can reduce I/R-induced ferroptosis via enhancing the Nrf2/SLC7A11 pathway. The SD rat hearts were subjected to 1h-ischemia plus 3h-reperfusion to establish the I/R injury model, which showed myocardial injuries (increase in infarct size and creatine kinase release) and up-regulation of MALT1 while downregulation of Nrf2 and SLC7A11 concomitant with the increased ferroptosis, reflecting by an increase in glutathione peroxidase 4 (GPX4) level while decreases in the levels of acyl-CoA synthetase long chain family member 4 (ACSL4), total iron, Fe2+ and lipid peroxidation (LPO); these phenomena were reversed in the presence of MI-2, a specific inhibitor of MALT1. Consistently, similar results were achieved in the cultured cardiomyocytes subjected to 8h-hypoxia plus 12h-reoxygenation. Furthermore, micafungin, an antifungal drug, could also exert beneficial effect on mitigating myocardial I/R injury via inhibition of MALT1. Based on these observations, we conclud that inhibition of MALT1 can reduce I/R-induced myocardial ferroptosis through enhancing the Nrf2/SLC7A11 pathway; and MALT1 may be used as a potential target to seek novel or existing drugs (such as micafungin) for treating myocardial infarction.
Assuntos
Ferroptose , Traumatismo por Reperfusão Miocárdica , Traumatismo por Reperfusão , Animais , Ratos , Isquemia , Micafungina , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Fator 2 Relacionado a NF-E2 , Ratos Sprague-Dawley , ReperfusãoRESUMO
INTRODUCTION: Breast cancer has become a common tumour that threatens women's physical and mental health. Microbial agents play an important role in maintaining the balance of gut microbiota and modulating intestinal immunity, anti-inflammatory and antioxidant effects. Available evidence points to a strong association between them and breast cancer. However, there has been no systematic review of the effects of microbial agents in patients with breast cancer. This protocol aims to explore the effectiveness and safety of probiotics, prebiotics and synbiotics in patients with breast cancer. METHODS AND ANALYSIS: We will search the following electronic databases for relevant randomised controlled trials: PubMed, EMBASE, Cochrane Library and Web of Science. Grey literature and reference lists of original studies will also be searched to avoid omissions. We will use the Cochrane Collaboration's Risk of Bias tool to assess the quality of the included studies. The primary outcomes include patients' arm oedema volume, changes in gut microbiota composition and anthropometric parameters. Two independent reviewers will perform literature screening, data extraction and risk of bias assessment. Data synthesis will be performed using descriptive analysis or meta-analysis. The quality of the evidence for each outcome will be assessed using the Grading of Recommendations Assessment, Development and Evaluation tool. ETHICS AND DISSEMINATION: The data for systematic reviews are derived from published original studies and do not require review and approval by the ethics committee. The results will be disseminated through a peer-reviewed journal and conferences. PROSPERO REGISTRATION NUMBER: CRD42022311502.
Assuntos
Neoplasias da Mama , Probióticos , Simbióticos , Feminino , Humanos , Neoplasias da Mama/terapia , Metanálise como Assunto , Prebióticos , Probióticos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Protocolos ClínicosRESUMO
AIMS: Immune checkpoint inhibitors (ICIs) have been recognized as an effective treatment for advanced gastric or gastroesophageal junction cancer (AG/GEJC). However, the safety of ICIs in patients has not been established. We aimed to systematically assess the risk of all common treatment-related adverse events (TRAEs) in immunotherapy of AG/GEJC. METHODS: A systematic search of randomized controlled trials (RCTs) published until May 2022 was performed using PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. And a meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: A total of nine RCTs, including 2918 patients, met the eligibility criteria. The pooled overall incidences of all grade TRAEs, grade 3 or higher TRAEs and treatment-related death were 54.5% (95% confidence interval [CI]: 48.7%-60.2%, I2=75.55%), 12.8% (95% CI: 10.2%-15.7%, I2=51.61%) and 0.11% (95% CI: 0.00%-0.51%, I2=1.63%). Subgroup analyses showed that CTLA-4 inhibitors had a higher risk of any type of TRAEs, when compared with PD-1 and PD-L1 inhibitors. Meta-regression showed significant correlation between all grade TRAEs and proportion of female. Fatigue and diarrhoea were involved in common TRAEs. CONCLUSIONS: Our study provides a comprehensive overview of ICIs-associated AEs in AG/GEJC. Immunotherapy did not have a significantly increased risk experiencing any type of TRAEs, and ICIs had a more manageable safety profile than chemotherapy. These findings provide important guidance to clinicians in counseling and management of patients with AG/GEJC.
Assuntos
Imunoterapia , Neoplasias Gástricas , Feminino , Humanos , Junção Esofagogástrica , Inibidores de Checkpoint Imunológico , Fatores Imunológicos/uso terapêutico , Imunoterapia/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Gástricas/tratamento farmacológico , MasculinoRESUMO
Ferroptosis is an iron-dependent cell death and contributes to doxorubicin-induced cardiotoxicity, but the mechanisms behind intracellular iron overload in cardiomyocyte after administration of doxorubicin remain largely unknown. Ferritinophagy is a selective type of autophagy and could be a novel source for intracellular free iron. Spermatogenesis-associated protein 2 (SPATA2), a member of the TNF signaling pathway, can recruit cylindromatosis (CYLD, a deubiquitinating enzyme) to regulate cell death. This study aims to explore whether ferritinophagy is the source for intracellular iron overload in cardiomyocyte upon doxorubicin treatment and whether the SPATA2/CYLD pathway is involved in regulation of nuclear receptor coactivator 4 (NCOA4) level, the selective cargo receptor for ferritinophagy. The C57BL/6J mice were subjected to a single injection of doxorubicin, which showed the compromised cardiac functions, accompanied by the upregulation of SPATA2 and CYLD and the enhanced interaction between them, the increases in ferritinophagy (reflecting by increases in NCOA4 and ratio of LC3â ¡/LC3â while decreases in NCOA4 ubiquitination and ferritin) and ferroptosis (reflecting by intracellular iron overload and increase of acyl-CoA synthetase long chain family member 4). Consistently, similar results were achieved in the cultured cardiomyocytes after incubation with doxorubicin. Knocked down of SPATA2 notably reduced doxorubicin-induced cardiomyocyte injury concomitant with the attenuated ferritinophagy and the decreased ferroptosis. Based on these observations, we conclude that a novel pathway of SPATA2/CYLD has been identified, which contributes to doxorubicin-induced cardiomyocyte ferroptosis via enhancing ferritinophagy through a mechanism involving the deubiquitination of NCOA4.
Assuntos
Ferroptose , Sobrecarga de Ferro , Camundongos , Masculino , Animais , Miócitos Cardíacos/metabolismo , Camundongos Endogâmicos C57BL , Autofagia , Ferro/metabolismo , Fatores de Transcrição , Doxorrubicina/toxicidade , Enzima Desubiquitinante CYLDRESUMO
In this work, a photobioreactor with microalgae biofilm was proposed to enhance CO2 biofixation and protein production using nickel foam with the modified surface as the carrier for immobilizing microalgae cells. The results demonstrated that, compared with microalgae suspension, microalgae biofilm lowered mass transfer resistance and promoted mass transfer efficiency of CO2 from the bubbles into the immobilized microalgae cells, enhancing CO2 biofixation and protein production. Moreover, parametric studies on the performance of the photobioreactor with microalgae biofilm were also conducted. The results showed that the photobioreactor with microalgae biofilm yielded a good performance with the CO2 biofixation rate of 4465.6 µmol m-3 s-1, the protein concentration of effluent liquid of 0.892 g L-1, and the protein synthesis rate of 43.11 g m-3 h-1. This work will be conducive to the optimization design of microalgae culture system for improving the performance of the photobioreactor.
Assuntos
Biofilmes/crescimento & desenvolvimento , Dióxido de Carbono/metabolismo , Microalgas/fisiologia , Níquel/química , Proteínas de Plantas/biossíntese , Scenedesmus/fisiologia , Proteínas de Membrana , FotobiorreatoresRESUMO
Baicalein is a flavonoid isolated from the roots of Scutellaria baicalensis Georgi. This study aimed to ascertain the effects and potential underlying mechanisms of baicalein in d-galactose (d-gal)-induced aging rat model by integration of behavior examination, biochemical detection, and 1H nuclear magnetic resonance (NMR)-based metabolomic approach. Our findings suggest that baicalein significantly attenuated memory decline in d-gal-induced aging model, as manifested by increasing recognition index in novel object recognition test, shortening latency time, and increasing platform crossings in Morris water maze test. Baicalein significantly inhibited the releases of inflammatory mediators such as nitric oxide, interleukin-6, interleukin-1 beta, and tumor necrosis factor-α in d-gal-induced aging model. Metabolomic study revealed that 10 endogenous metabolites in cerebral cortex were considered as potential biomarkers of baicalein for its protective effect. Further metabolic pathway analysis showed that the metabolic alterations were associated with alanine, aspartate and glutamate metabolism, glycine, serine and threonine metabolism, inositol phosphate metabolism, and energy metabolism. These data indicate that baicalein improves learning and memory dysfunction in d-gal-induced aging rats. This might be achieved through attenuation of inflammation and metabolic dysfunction.
Assuntos
Envelhecimento/metabolismo , Flavanonas/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Envelhecimento/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Análise Discriminante , Comportamento Alimentar/efeitos dos fármacos , Flavanonas/farmacologia , Galactose , Inflamação/sangue , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Análise dos Mínimos Quadrados , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica , Análise Multivariada , Análise de Componente Principal , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-DawleyRESUMO
Traditional Chinese medicine (TCM) has been used to treat tumors for years and has been demonstrated to be effective. However, the underlying molecular mechanisms of herbs remain unclear. This study aims to ascertain molecular targets of herbs prolonging survival time of patients with advanced hepatocellular carcinoma (HCC) based on network pharmacology, and to establish a research method for accurate treatment of TCM. The survival benefit of TCM treatment with Chinese herbal medicine (CHM) was proved by Kaplan-Meier method and Cox regression analysis among 288 patients. The correlation between herbs and survival time was performed by bivariate correlation analysis. Network pharmacology method was utilized to construct the active ingredient-target networks of herbs that were responsible for the beneficial effects against HCC. Cox regression analysis showed CHM was an independent favorable prognostic factor. The median survival time was 13 months and the 5-year overall survival rates were 2.61% in the TCM group, while there were 6 months, 0 in the non-TCM group. Correlation analysis demonstrated that 8 herbs closely associated with prognosis. Network pharmacology analysis revealed that the 8 herbs regulated multiple HCC relative genes, among which the genes affected proliferation (KRAS, AKT2, MAPK), metastasis (SRC, MMP), angiogenesis (PTGS2) and apoptosis (CASP3) etc.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Plantas Medicinais , Perfilação da Expressão Gênica , Humanos , Testes Farmacogenômicos , Análise de Sobrevida , Resultado do TratamentoRESUMO
AIM: To evaluate the relationship between glutathione S-transferase M1 (GSTM1) polymorphism and susceptibility to esophageal cancer (EC). METHODS: A comprehensive search of the United States National Library of Medicine PubMed database and the Elsevier, Springer, and China National Knowledge Infrastructure databases for all relevant studies was conducted using combinations of the following terms: "glutathione S-transferase M1", "GSTM1", "polymorphism", and "EC" (until November 1, 2014). The statistical analysis was performed using the SAS software (v.9.1.3; SAS Institute, Cary, NC, United States) and the Review Manager software (v.5.0; Oxford, England); crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between the GSTM1 null genotype and the risk of EC. RESULTS: A total of 37 studies involving 2236 EC cases and 3243 controls were included in this meta-analysis. We observed that the GSTM1 null genotype was a significant risk factor for EC in most populations (OR = 1.33, 95%CI: 1.12-1.57, P heterogeneity < 0.000001, and I (2) = 77.0%), particularly in the Asian population (OR = 1.53, 95%CI: 1.26-1.86, P heterogeneity < 0.000001, and I (2) = 77.0%), but not in the Caucasian population (OR = 1.02, 95%CI: 0.87-1.19, P heterogeneity = 0.97, and I (2) = 0%). CONCLUSION: The GSTM1 null polymorphism may be associated with an increased risk for EC in Asian but not Caucasian populations.
Assuntos
Neoplasias Esofágicas/genética , Glutationa Transferase/genética , Polimorfismo Genético , Povo Asiático/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/enzimologia , Neoplasias Esofágicas/epidemiologia , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Razão de Chances , Fenótipo , Medição de Risco , Fatores de RiscoRESUMO
Intracranial aneurysms (IAs) accounts for 85% of hemorrhagic stroke. Genetic factors have been known to play an important role in the development of IAs. A functional CNV (CNV-67048) of human WW domain-containing oxidoreductase (WWOX), which has been identified as a tumor suppressor gene in multiple cancers, was identified to be associated with gliomas risk previously. Here, we hypothesized that the CNV-67048 could also affect susceptibility of IAs. Based on a two-stage, case- control study with a total of 976 patients of IAs and 1,200 matched healthy controls, we found the effect size for per copy deletion was 1.35 (95% CI = 1.16-1.57; Ptrend = 1.18 × 10-4). Compared with the individuals having no deletion, significantly higher risk of IAs was detected for both subjects carrying 1 copy deletion (OR = 1.24, 95% CI = 1.02-1.52) and subjects carrying 2 copy deletion (OR = 1.77, 95% CI = 1.24-2.53). Real-time PCR was used to confirm the abnormal expression of WWOX in tissues of IA patients and influence of genotypes of CNV-67048. The expression level of WWOX in IA tissues was significantly lower than that in corresponding normal tissues (P = 0.004), and the deletion genotypes of CNV-67048 have lower WWOX mRNA levels in both tumor tissues and border tissues (P < 0.01). Our data suggests that the deletion genotypes of CNV-67048 in WWOX predispose their carriers to IAs, which might be a genetic biomarker to predict risk of IAs in Chinese.
Assuntos
Predisposição Genética para Doença/genética , Aneurisma Intracraniano/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , Adulto , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , Variações do Número de Cópias de DNA/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
To determine whether computed tomography perfusion imaging (CTPI)-derived parameters are associated with vascular cognitive impairment (VCI) in patients with transient ischemic attack (TIA). Patients with first-time anterior circulation TIA (diagnosed within 24 h of onset) and normal cognition, treated between August 2009 and August 2014 at the Department of Neurology of Chengdu Military General Hospital, China, were analyzed retrospectively. Patients underwent whole-brain CTPI within 1 week of TIA to detect cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT) and time to peak (TTP) in the ischemic region. Based on cognitive function assessment 4 weeks after TIA, using the Montreal cognitive assessment (MoCA) and mini mental state examination, the patients were divided into control and VCI groups. CTPI parameters and other clinical data were compared between groups, and Spearman's correlation analysis used to identify associations between cognitive scores and CTPI parameters in the VCI group. 50 patients (25 per group; aged 55-72 years) were included. Patient age, gender, smoking status, alcohol consumption, educational level, time from TIA onset to admission, time from TIA onset to CTPI, and prevalence of hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation and hyperhomocysteinemia did not differ between groups. Both groups showed TTP and MTT prolongation, CBF reduction, but no change in CBV in the ischemic region; these changes were significantly larger in the VCI group (P < 0.05). MTT correlated negatively with MoCA score (r = -0.51, P = 0.009). CTPI could facilitate early diagnosis of VCI in patients with anterior circulation TIA.
Assuntos
Angiografia Cerebral/métodos , Transtornos Cognitivos/etiologia , Cognição , Angiografia por Tomografia Computadorizada , Circulação Coronária , Ataque Isquêmico Transitório/diagnóstico por imagem , Imagem de Perfusão/métodos , Idoso , Velocidade do Fluxo Sanguíneo , Volume Sanguíneo , China , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Diagnóstico Precoce , Feminino , Humanos , Ataque Isquêmico Transitório/complicações , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de RiscoRESUMO
Synaptic dysfunction underlies cognitive deficits induced by chronic cerebral hypoperfusion (CCH). There are silent synapses in neural circuits, but the effect of CCH on silent synapses is unknown. The present study was designed to explore learning and memory deficits and dynamic changes in silent synapses by direct visualization in a rat model of CCH. Adult male Sprague-Dawley rats were subjected to permanent bilateral common carotid artery occlusion (BCCAO) to reproduce CCH. Learning and memory effects were examined at 1, 4, 12, and 24 weeks after BCCAO. In addition, immunofluorescent confocal microscopy was used to detect AMPA and N-methyl-d-aspartate receptors colocalized with synaptophysin, and Golgi-Cox staining was used to observe dendritic spine density. We found that BCCAO rats exhibited recognition memory deficits from 4 weeks; spatial learning and memory, as well as working memory impairment began at 1 week and persistent to 24 weeks after surgery. Following BCCAO, the percentage of silent synapses increased by 29.81-55.08% compared with the controls at different time points (P<0.001). Compared with control groups, dendritic spine density in the CA1 region of BCCAO groups significantly decreased (P<0.001). Thus, the present study suggests that CCH can induce long-lasting cognitive deficits and long-term increase in the number of silent synapses. Furthermore, the decrease in dendritic spine density was correlated with the decrease in the number of functional synapses. The results suggest a potential mechanism by which CCH can induce learning and memory deficits.
Assuntos
Transtornos Cerebrovasculares/fisiopatologia , Transtornos Cognitivos/fisiopatologia , Hipocampo/fisiopatologia , Sinapses/fisiologia , Animais , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/patologia , Transtornos Cerebrovasculares/psicologia , Doença Crônica , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Modelos Animais de Doenças , Imunofluorescência , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/fisiologia , Memória de Curto Prazo/fisiologia , Microscopia Confocal , Células Piramidais/patologia , Células Piramidais/fisiologia , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Reconhecimento Psicológico/fisiologia , Memória Espacial/fisiologia , Sinapses/patologia , Sinaptofisina/metabolismoRESUMO
In order to explore the anti-aging effect of baicalein, female Drosophila melanogaster as a model organism was used to study the effects of baicalein on natural aging model and aging models induced by hydrogen peroxideï¼H2O2ï¼ and paraquat. The bioinformatics approach was used to predict the possible target for the anti-aging activity of baicalein, and the target pathways were identified. The oxidative stress pathway was a focus in experiment. Baicalein at concentrations of 0.04 mg·m L-1 and 0.2 mg·m L-1 extended the mean and maximum lifespans in the natural aging model, and effectively reduced the damages of oxidative stress by H2O2 and paraquat. 31 senescence-related targets together with the oxidative stress pathway were modulated by baicalein. The experiments revealed that baicalein might delay aging process through attenuation of the oxidative stress response by decreasing the reactive oxygen speciesï¼ROSï¼, malondialdehydeï¼MDAï¼ and oxidized glutathioneï¼GSSGï¼ in Drosophila melanogaster.
Assuntos
Drosophila melanogaster/efeitos dos fármacos , Flavanonas/farmacologia , Longevidade/efeitos dos fármacos , Estresse Oxidativo , Animais , Feminino , Glutationa/metabolismo , Peróxido de Hidrogênio , Malondialdeído/metabolismo , Paraquat , Espécies Reativas de Oxigênio/metabolismoRESUMO
Scl/Tal1 confers hemogenic competence and prevents ectopic cardiomyogenesis in embryonic endothelium by unknown mechanisms. We discovered that Scl binds to hematopoietic and cardiac enhancers that become epigenetically primed in multipotent cardiovascular mesoderm, to regulate the divergence of hematopoietic and cardiac lineages. Scl does not act as a pioneer factor but rather exploits a pre-established epigenetic landscape. As the blood lineage emerges, Scl binding and active epigenetic modifications are sustained in hematopoietic enhancers, whereas cardiac enhancers are decommissioned by removal of active epigenetic marks. Our data suggest that, rather than recruiting corepressors to enhancers, Scl prevents ectopic cardiogenesis by occupying enhancers that cardiac factors, such as Gata4 and Hand1, use for gene activation. Although hematopoietic Gata factors bind with Scl to both activated and repressed genes, they are dispensable for cardiac repression, but necessary for activating genes that enable hematopoietic stem/progenitor cell development. These results suggest that a unique subset of enhancers in lineage-specific genes that are accessible for regulators of opposing fates during the time of the fate decision provide a platform where the divergence of mutually exclusive fates is orchestrated.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/fisiologia , Elementos Facilitadores Genéticos/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Células-Tronco Hematopoéticas/citologia , Mesoderma/embriologia , Mioblastos Cardíacos/citologia , Proteínas Proto-Oncogênicas/metabolismo , Células Cultivadas , Imunoprecipitação da Cromatina , Perfilação da Expressão Gênica , Biblioteca Gênica , Células-Tronco Hematopoéticas/fisiologia , Humanos , Mesoderma/metabolismo , Análise em Microsséries , Modelos Biológicos , Dados de Sequência Molecular , Mioblastos Cardíacos/fisiologia , Análise de Sequência de RNA , Proteína 1 de Leucemia Linfocítica Aguda de Células TRESUMO
Endothelial cells and macrophages are known to engage in tight and specific interactions that contribute to the modulation of vascular function. Here we show that adult endothelial cells provide critical signals for the selective growth and differentiation of macrophages from several hematopoietic progenitors. The process features the formation of well-organized colonies that exhibit progressive differentiation from the center to the periphery and toward an M2-like phenotype, characterized by enhanced expression of Tie2 and CD206/Mrc1. These colonies are long-lived depending on the contact with the endothelium; removal of the endothelial monolayer results in rapid colony dissolution. We further found that Csf1 produced by the endothelium is critical for the expansion of the macrophage colonies and that blockade of Csf1 receptor impairs colony growth. Functional analyses indicate that these macrophages are capable of accelerating angiogenesis, promoting tumor growth, and effectively engaging in tight associations with endothelial cells in vivo. These findings uncover a critical role of endothelial cells in the induction of macrophage differentiation and their ability to promote further polarization toward a proangiogenic phenotype. This work also highlights some of the molecules underlying the M2-like differentiation, a process that is relevant to the progression of both developmental and pathologic angiogenesis.
Assuntos
Diferenciação Celular , Endotélio Vascular/patologia , Macrófagos/patologia , Neovascularização Patológica/patologia , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/patologia , Animais , Endotélio Vascular/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Células Progenitoras Mieloides/metabolismo , Células Progenitoras Mieloides/patologia , Fenótipo , Neoplasias da Próstata/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Hepatocellular carcinoma (HCC) is one of the most deadly human cancers. Chronic hepatitis B virus (HBV) infection is one of the predominant risk factors associated with the development of HCC and complicates the treatment of HCC. In this study, we demonstrate that a HBV-positive HCC cell line HepG2.2.15, was more resistant to chemotherapy agents than its parental HBV-negative cell line HepG2. HBV-positive HCC cells exhibited defective Chk1 phosphorylation and increased chromosomal instability. CGK733, a small molecule inhibitor reportedly targeting the kinase activities of ATM and ATR, significantly enhanced taxol-induced cytotoxicity in HBV-positive HepG2.2.15 cells. The mechanism lies in CGK733 triggers the formation of multinucleated cells thus promotes the premature mitotic exit of taxol-induced mitotic-damaged cells through multinucleation and mitotic catastrophe in HBV-positive HepG2.2.15 cells. These results suggest that CGK733 could potentially reverse the taxol resistance in HBV-positive HCC cells and may suggest a novel strategy to treat HBV-infected HCC patients.