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Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), pose significant global health risks and represent a substantial public health concern in the contemporary era. A primary factor in the pathophysiology of these disorders is aberrant accumulation and aggregation of pathogenic proteins within the brain and spinal cord. Recent investigations have identified extracellular vesicles (EVs) in the central nervous system (CNS) as potential carriers for intercellular transport of misfolded proteins associated with neurodegenerative diseases. EVs are involved in pathological processes that contribute to various brain disorders including neurodegenerative disorders. Proteins linked to neurodegenerative disorders are secreted and distributed from cell to cell via EVs, serving as a mechanism for direct intercellular communication through the transfer of biomolecules. Astrocytes, as active participants in CNS intercellular communication, release astrocyte-derived extracellular vesicles (ADEVs) that are capable of interacting with diverse target cells. This review primarily focuses on the involvement of ADEVs in the development of neurological disorders and explores their potential dual roles - both advantageous and disadvantageous in the context of neurological disorders. Furthermore, this review examines the current studies investigating ADEVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases. The prospects and challenges associated with the application of ADEVs in clinical settings were also comprehensively reviewed.
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Cancer, a prevalent and complex disease, presents a significant challenge to the medical community. It is characterized by irregular cell differentiation, excessive proliferation, uncontrolled growth, invasion of nearby tissues, and spread to distant organs. Its progression involves a complex interplay of several elements and processes. Extracellular vesicles (EVs) serve as critical intermediaries in intercellular communication, transporting critical molecules such as lipids, RNA, membrane, and cytoplasmic proteins between cells. They significantly contribute to the progression, development, and dissemination of primary tumors by facilitating the exchange of information and transmitting signals that regulate tumor growth and metastasis. However, EVs do not have a singular impact on cancer; instead, they play a multifaceted dual role. Under specific circumstances, they can impede tumor growth and influence cancer by delivering oncogenic factors or triggering an immune response. Furthermore, EVs from different sources demonstrate distinct advantages in inhibiting cancer. This research examines the biological characteristics of EVs and their involvement in cancer development to establish a theoretical foundation for better understanding the connection between EVs and cancer. Here, we discuss the potential of EVs from various sources in cancer therapy, as well as the current status and future prospects of engineered EVs in developing more effective cancer treatments.
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Vesículas Extracelulares , Neoplasias , Vesículas Extracelulares/metabolismo , Humanos , Neoplasias/terapia , Neoplasias/patologia , Neoplasias/metabolismo , Comunicação Celular , AnimaisRESUMO
Circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and extracellular vehicles (EVs) have received significant attention in recent times as emerging biomarkers and subjects of transformational studies. The three main branches of liquid biopsy have evolved from the three primary tumor liquid biopsy detection targets-CTC, ctDNA, and EVs-each with distinct benefits. CTCs are derived from circulating cancer cells from the original tumor or metastases and may display global features of the tumor. ctDNA has been extensively analyzed and has been used to aid in the diagnosis, treatment, and prognosis of neoplastic diseases. EVs contain tumor-derived material such as DNA, RNA, proteins, lipids, sugar structures, and metabolites. The three provide different detection contents but have strong complementarity to a certain extent. Even though they have already been employed in several clinical trials, the clinical utility of three biomarkers is still being studied, with promising initial findings. This review thoroughly overviews established and emerging technologies for the isolation, characterization, and content detection of CTC, ctDNA, and EVs. Also discussed were the most recent developments in the study of potential liquid biopsy biomarkers for cancer diagnosis, therapeutic monitoring, and prognosis prediction. These included CTC, ctDNA, and EVs. Finally, the potential and challenges of employing liquid biopsy based on CTC, ctDNA, and EVs for precision medicine were evaluated.
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BACKGROUND: Resistance can develop during treatment of advanced endometrial cancer (EC), leading to unsatisfactory results. Fanconi anemia complementation group D2 (Fancd2) has been shown to be closely related to drug resistance in cancer cells. Therefore, this study was designed to explore the correlation of Fancd2 with EC resistance and the mechanism of Fancd2. METHODS: Real-time quantitative PCR (RT-qPCR) was used to detect the expression of Fancd2 in EC tissues and cells. EC cells (Ishikawa) and paclitaxel-resistant EC cells (Ishikawa/TAX) were transfected to knock down Fancd2. In addition, the ferroptosis inhibitor Ferrostatin-1 was adopted to treat Ishikawa/TAX cells. The sensitivity of cancer cells to chemotherapeutic agents was observed via 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and inhibitory concentration (IC)50 was calculated. Reactive oxygen species (ROS) levels were measured by flow cytometry, the activity of malondialdehyde (MDA) and the levels of glutathione (GSH) and Fe2+ in cells were detected by corresponding kits, and protein expression of solute farrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) was obtained through western blot. RESULTS: Compared with the normal tissues and endometrial epithelial cells, Fancd2 expression was significantly increased in EC tissues and Ishikawa cells, respectively. After knock-down of Fancd2, Ishikawa cells showed significantly increased sensitivity to chemotherapeutic agents. Besides, compared with Ishikawa cells, the levels of ROS, the activity of MDA, and the levels of GSH and Fe2+ were significantly decreased in Ishikawa/TAX cells, while the expression levels of SLC7A11 and GPX4 were significantly increased. Knock-down of Fancd2 significantly increased the ferroptosis levels in Ishikawa/TAX cells, but this effect could be reversed by Ferrostatin-1. CONCLUSION: Fancd2 increases drug resistance in EC cells by inhibiting the cellular ferroptosis pathway.
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Cicloexilaminas , Neoplasias do Endométrio , Anemia de Fanconi , Ferroptose , Fenilenodiaminas , Feminino , Humanos , Espécies Reativas de Oxigênio/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genéticaRESUMO
OBJECTIVE: Some studies have reported that the prognosis of total laparoscopic hysterectomy (TLH) for early-stage cervical cancer (CC) is worse than that of open surgery. And this was associated with the use of uterine manipulator or not. Therefore, this study retrospectively analyzes the efficacy and safety of TLH without uterine manipulator combined with pelvic lymphadenectomy for early-stage CC. METHODS: Fifty-eight patients with CC (stage IB1-IIA1) who received radical hysterectomy from September 2019 to January 2020 were divided into no uterine manipulator (n = 26) and uterine manipulator group (n = 32). Then, clinical characteristics were collected and intraoperative/postoperative related indicators were compared. RESULTS: Patients in the no uterine manipulator group had significantly higher operation time and blood loss than in the uterine manipulator group. Notably, there was no significant difference in hemoglobin change, blood transfusion rate, number of pelvic nodules, anal exhaust time, complications and recurrence rate between the two groups. Additionally, patients in the uterine manipulator group were prone to urinary retention (15.6%) and lymphocyst (12.5%), while the no uterine manipulator group exhibited high probability of bladder dysfunction (23.1%) and urinary retention (15.4%). Furthermore, the 1-year disease-free survival rate and the 1-year overall survival rate were not significantly different between the two groups. CONCLUSION: There was no significant difference in the efficacy and safety of TLH with or without uterine manipulator combined with pelvic lymphadenectomy in the treatment of patients with early-stage CC. However, the latter requires consideration of the negative effects of high operation time and blood loss.
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Histerectomia , Laparoscopia , Retenção Urinária , Neoplasias do Colo do Útero , Feminino , Humanos , Histerectomia/efeitos adversos , Laparoscopia/efeitos adversos , Excisão de Linfonodo/efeitos adversos , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgiaRESUMO
Research shows an association between vaginal microbiota and the development of cervical cancer, but the role of altered microbiota in cancer development remains controversial. In this study, we attempted to reveal the vaginal microecological changes in cervical lesions by 16S rRNA gene sequencing. Vaginal secretions were collected from Hakka women in Meizhou City, Guangdong Province, China. The diversity, composition and the correlations among species of the vaginal microbiota were determined by sequencing the bacterial 16S rRNA gene. The microbial functional abundance was detected via KEGG and COG (Clusters of Orthologous Groups). The results showed that the Cancer group was characterised by evident changes in the composition of the vaginal microbiota, increased alpha diversity, and altered community structure distribution and microbial interaction network. Linear discriminant analysis (LDA) effect size showed that 21 bacterial species were abundant in the Cancer group. In addition, the loss of Lactobacillus stimulated other flora proliferation, resulting in a microecological disturbance. KEGG and COG analysis indicated the cancer group is mainly concentrated in energy metabolism. In short, the vaginal microecology of Hakka women in Meizhou City presents with different degrees of cervical lesions, and the flora imbalance is an important factor in the development of cervical cancer.IMPACT STATEMENTWhat is already known on this subject? Cervical cancer is one of the most common gynecological malignancies worldwide and has become a prominent public health problem.What the results of this study add? Our study showed that the type of vaginal community status of Hakka women in Meizhou area was characterised by L. Iners predominates, and the gradual loss of Lactobacillus dominance in vaginal bacteria is key to microecological imbalance.What the implications are of these findings for clinical practice and/or further research? Disturbances in vaginal microecology can stimulate energy metabolism and lipid metabolism to induce cervical cancer development.
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Microbiota , Neoplasias do Colo do Útero , Feminino , Humanos , RNA Ribossômico 16S/genética , Vagina/microbiologia , Lactobacillus/genética , Microbiota/genéticaRESUMO
This study aims to observe the differentiating effect of shikonin on Wilms' tumor 1 (WT1)-positive HL-60 cells and investigate the fate of the differentiated leukemia cells. WT1 overexpression unaffected cell viability but promoted resistance to H2O2-induced DNA injury and cell apoptosis. The binding of shikonin to the WT1 protein was confirmed by molecular docking and drug affinity reaction target stability (DARTS). Shikonin at the non-cytotoxic concentration could decrease the WT1 protein and simultaneously reduced the CD34 protein and increased the CD11b protein in a dose-dependent manner in normal HL-60 cells but not in WT1-overexpressed HL-60 cells. Shikonin unaffected HL-60 cell viability in 48 h. However, it lasted for 10 days; could attenuate cell proliferation, mitochondrial membrane potential (MMP), and self-renewal; prevent the cell cycle; promote cell apoptosis. In a mouse leukemia model, shikonin could decrease the WT1 protein to prevent leukemia development in a dose-dependent manner. In this study, we also confirmed preliminarily the protein-protein interactions between WT1 and CD34 in molecular docking and CO-IP assay. Our results suggest that: 1. shikonin can down-regulate the WT1 protein level for leukemia differentiation therapy, and 2. the interaction between WT1 and CD34 proteins may be responsible for granulocyte/monocyte immaturity in HL-60 cells.
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Leucemia , Proteínas WT1 , Animais , Camundongos , Proteínas WT1/genética , Simulação de Acoplamento Molecular , Peróxido de Hidrogênio/farmacologia , Leucemia/metabolismo , Diferenciação Celular , Antígenos CD34/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Mufangji decoction (MFJD), a famous traditional Chinese medicine formula in Synopsis of Golden Chamber (Jingui yaolue), has been utilized to treat cough and asthma and release chest pain over 2000 years in China. Chinese old herbalist doctor use MFJD to treat lung cancer and cancerous pleural fluid, but the preventive effect of MFJD on lung cancer and the underlying mechanism are indefinite. AIM OF THE STUDY: The goal of this study is to explore the efficacy and mechanism of Mufangji decoction preventing lung cancer referring to the traditional use. MATERIALS AND METHODS: Tumor allograft experiment and host versus tumor experiment were used to observe the direct anti-tumor effect and indirect anti-tumor immune effect, the mouse lung carcinogenic model was used to evaluate the dose-response and the preventive effect of MFJD on lung cancer. The active ingredients of MFJD were obtained by UPLC-MS/MS. The potential targets of MFJD were screened by network pharmacology and transcriptomics. The therapeutic targets and pathways of MFJD on lung cancer were obtained by protein-protein interaction, molecular docking and David database. The predicted results were verified in vitro and in vivo. RESULTS: MFJD could significantly prevent tumor growth in host versus tumor experiment but could not in tumor allograft experiment, indicating an anti-tumor immune effect against lung cancer. MFJD could reduce lung nodules with a dose-response in mouse lung carcinogenic model. Myeloperoxidase (MPO) was selected as the core target due to the highest degree value in Protein-Protein interaction network and had potently binding activity to sinomenine and dehydrocostus lactone in molecular docking. In vivo, MPO-expressed neutrophils are negatively correlated with lung cancer progression and MFJD could promote the neutrophil-related immune surveillance. In vitro, sinomenine and dehydrocostus lactone could promote neutrophil phagocytosis, MPO and ROS production in a dose dependent manner. The major compounds from MFJD were identified to regulate 36 targets for lung cancer prevention by UPLC-MS/MS, network pharmacology and transcriptomics. David database exhibited that MFJD plays an important role in immunoregulation by modulating 4 immune-related biological processes and 3 immune-related pathways. CONCLUSIONS: MFJD prevents lung cancer by mainly promoting MPO expression to maintain neutrophil immune surveillance, its key compounds are sinomenine and dehydrocostus lactone.
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Medicamentos de Ervas Chinesas , Neoplasias Pulmonares , Animais , Cromatografia Líquida , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/prevenção & controle , Camundongos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Espectrometria de Massas em Tandem , TranscriptomaRESUMO
BACKGROUND Cervical cancer is the fourth most commonly diagnosed malignant neoplasm among women worldwide. Despite improvements in treatment, the rate of postoperative metastasis remains a problem. Nomograms have been used to predict risk of tumor metastasis. We designed a nomogram to predict postoperative distant metastasis among cervical cancer patients, based on the SEER database, and estimated the performance of the nomogram by internal and external validations. MATERIAL AND METHODS We included 6421 participants and divided them into training (n=4495) and testing (n=1926) sets. Multivariate logistic regression was used to explore predictors. The nomogram's predictive value was assessed by internal (testing set) and external (561 Chinese patients) validations. The receiver operating characteristic curve (ROC) was plotted, and the area under the curve (AUC) value was calculated to evaluate the nomogram's discrimination. The nomogram's calibration was assessed via the Hosmer-Lemeshow test and calibration curve. RESULTS Histologic type, T stage, treatment, tumor size, and positive lymph node were identified as independent predictors of postoperative distant metastasis in surgical patients (P<0.05). The developed nomogram had an AUC of 0.866 (95% CI: 0.844 to 0.888). The AUC and the chi-square for the Hosmer-Lemeshow test of the nomogram were 0.847 (95% CI: 0.807 to 0.888) and 11.292, respectively, (P>0.05) in the internal validation, and were 0.626 (95% CI: 0.548 to 0.704) and 316.53, respectively, (P<0.05) in the external validation. CONCLUSIONS Our nomogram showed a good predictive performance for postoperative distant metastasis in cervical cancer patients based on the SEER database. It remains to be determined if it is applicable to other populations.
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Nomogramas , Neoplasias do Colo do Útero , Área Sob a Curva , Feminino , Humanos , Metástase Linfática , Curva ROC , Neoplasias do Colo do Útero/cirurgiaRESUMO
PURPOSE: This study aimed to analyze left ventricular (LV) remodeling in patients with LV dilation using three-dimensional (3D) echocardiography, and to compare geometry and systolic function between patients with dilated cardiomyopathy (DCM) and with mitral regurgitation (MR) but similar LV dimension. METHODS: Cross-sectional study of 60 DCM and 60 MR patients with LV end diastolic diameter (LVEDD) > 35 mm/m2 , and of 60 healthy control volunteers. RESULTS: Despite a similar LVEDD, DCM patients showed a significantly higher 3D sphericity index (3D-SI) than MR patients, whereas 3D ejection fraction (3D-EF) was significantly lower (P < .01). There was a linear relationship between 3D-EF and 3D-SI in both DCM and MR patients (r = -0. 745 and r = -0. 642, respectively; both P < .001). Receiver operating characteristic (ROC) curves showed that 3D-SI had could better discriminate between DCM and MR (sensitivity 90%; specificity 73%; AUC 0.852, P < .01) than other variables. The area under the ROC curve of 3D-SI was significantly larger than that of 3D-EF for detecting heart failure in both patients with DCM and MR. CONCLUSIONS: LV geometry appears to be more spherical and associated with worse systolic function in DCM than in MR patients, in spite of similar LV dimensions. Systolic function correlated significantly with 3D-SI, which provided a better description of LV remodeling and could be a stronger indicator of heart failure in patients with LV dilation.
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Cardiomiopatia Dilatada/diagnóstico por imagem , Ecocardiografia Tridimensional , Ventrículos do Coração/diagnóstico por imagem , Insuficiência da Valva Mitral/diagnóstico por imagem , Disfunção Ventricular Esquerda/diagnóstico por imagem , Remodelação Ventricular , Adulto , Cardiomiopatia Dilatada/fisiopatologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/fisiopatologia , Sensibilidade e Especificidade , Disfunção Ventricular Esquerda/etiologiaRESUMO
Dilated cardiomyopathy (DCM) is considered as the final common response of myocardium to diverse genetic and environmental insults and characterized mainly by left ventricular systolic dysfunction. The current therapies for the treatment of DCM are costly high and outcomes are often unsatisfactory. To date, mesenchymal stem cells (MSCs) have been thought to be an ideal stem cell to repair damaged myocardium but was still within relatively small scales and few cases have been conducted in clinical trials. The use of erythropoietin (EPO), a growth factor produced in the kidneys have been found prevent cardiomyocyte apoptosis. This study was aimed to transplant MSCs into DCM rat bone marrow to express EPO in vivo and investigate the regulation of EPO on cell signaling pathways after transfection. The results found that transplantation of MSCs carrying EPO could significantly relief the cardiac dysfunctions of the DCM rat. This underylying mechanism involved with inhibiting p-NF-κB and p-P38, regulateing and promoting the anti-inflammatory balance, thereby alleviating tissue injury in DCM rats and exhibiting a protective role. Meanwhile, the MSCs + EPO treatment in DCM rat also activated the p-Akt pathway and thus protecting the myocardium from apoptosis in DCM rats. The study revealed an potential therapeutic effect of MSCs and EPO in clinical and provided a molecular mechanism of action for treating DCM.
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Cardiomiopatia Dilatada/terapia , Eritropoetina/uso terapêutico , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Animais , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/fisiopatologia , Testes de Função Cardíaca , Hemodinâmica , Células-Tronco Mesenquimais/ultraestrutura , Miocárdio/metabolismo , Miocárdio/patologia , Miocárdio/ultraestrutura , Fosforilação , Ratos Endogâmicos LewRESUMO
BACKGROUND: Hypercoagulation and neutrophilia are described in several cancers, however, whether they are involved in lung carcinogenesis is currently unknown. Emodin is the main bioactive component from Rheum palmatum and has many medicinal values, such as anti-inflammation and anticancer. This study is to investigate the contributions of neutrophils to the effects of emodin on hypercoagulation and carcinogenesis. METHODS: The effects of emodin on neutrophil phenotypes were assessed by cell proliferation, morphological changes, phagocytosis and autophagy in vitro. The anti-coagulation and cancer-preventing actions of emodin were evaluated in the urethane-induced lung carcinogenic model. The expressions of Cit-H3 and PAD4 in lung sections were assessed by immunohistochemistry, CD66b+ neutrophils were distinguished by immunofluorescence, and cytokines and ROS were examined with ELISA. The neutrophils-regulating and hypercoagulation-improving efficacies of emodin were confirmed in a Lewis lung cancer allograft model. The related targets and pathways of emodin were predicted by network pharmacology. RESULTS: In vitro, emodin at the dose of 20 µM had no effect on cell viability in HL-60N1 but increased ROS and decreased autophagy and thus induced apoptosis in HL-60N2 with the morphological changes. In the urethane-induced lung carcinogenic model, before lung carcinogenesis, urethane induced obvious hypercoagulation which was positively correlated with lung N2 neutrophils. There were the aggravated hypercoagulation and lung N2 neutrophils after lung carcinoma lesions. Emodin treatment resulted in the ameliorated hypercoagulation and lung carcinogenesis accompanied by the decreased N2 neutrophils (CD66b+) in the alveolar cavity. ELISA showed that there were more IFN-γ, IL-12 and ROS and less IL-6, TNF-α and TGF-ß1 in the alveolar cavity in the emodin group than those in the control group. Immunohistochemical analysis showed that emodin treatment decreased Cit-H3 and PAD4 in lung sections. In the Lewis lung cancer allograft model, emodin inhibits tumor growth accompanied by the attenuated coagulation and intratumor N2 neutrophils. Network pharmacology indicated the multi-target roles of emodin in N2 neutrophil activation. CONCLUSIONS: This study suggests a novel function of emodin, whereby it selectively suppresses N2 neutrophils to prevent hypercoagulation and lung carcinogenesis.
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Transtornos da Coagulação Sanguínea/tratamento farmacológico , Transtornos da Coagulação Sanguínea/prevenção & controle , Carcinogênese/patologia , Emodina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/prevenção & controle , Neutrófilos/patologia , Aloenxertos/efeitos dos fármacos , Animais , Carcinogênese/efeitos dos fármacos , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/patologia , Emodina/farmacologia , Armadilhas Extracelulares/metabolismo , Feminino , Células HL-60 , Humanos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Neutrófilos/efeitos dos fármacos , Fenótipo , Mapas de Interação de Proteínas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , UretanaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Arsenic trioxide (As2O3), a main component of arsenolite which is a common traditional Chinese medicine (TCM) wildly used as a therapeutic agent for more than 2400 years in china, has been accepted as a standard treatment for the patients with acute promyelocytic leukemia (APL) based on the principle in TCM of "using a poison to fight against other poisons or malignancy illnesses". However, it remains unknown that which mechanism is actually responsible for the therapeutic effects against these blood malignancies. AIM OF THE STUDY: The purpose of this study was to explore the actual mechanism that ATO exerts its effects in K562 cells and their initiating cells (K562s). MATERIALS AND METHODS: K562s cells were separated and enriched for CD34+/CD38- cells using magnetic microbeads. Cell proliferation was determined by incorporation of BrdU. Cell apoptosis was evaluated by Annexin-V binding and PI uptake. Autophagy was estimated by acridine orange and immunofluorescence staining of LC3-B and p62. MC colonic formation was used to examine cell self-renew. ROS generation inside living cells was measured by DCFH-DA. Cell differentiation was assessed by the benzidine staining. The SA-ß-gal assay was used to detect cell senescence. Protein expression was examined by western blotting and immunohistochemical staining. RESULTS: K562s cells were stronger in self-renew and resistance to ATO cytotoxicity and starvation-induced apoptosis than K562 cells. Unexpectedly, we found that ATO at a dose of 0.5µM which had no effect on cell proliferation resulted in maximum suppression on self-renew in both cells and maximum starvation-induced apoptosis in K562s cells but minimum starvation-induced apoptosis in K562 cells. Next, we found that ATO no more than 0.5µM selectively induced K562s cell differentiation indicated by benzidine staining, γ-globin and CD235a expression. More importantly, we found that ATO no more than 0.5µM led to opposite efficacy in autophagy between K562 and K562s cells, and the opposite autophagy could induced late-phase senescence in both cells. Finally, we used the optimal dose of ATO to eradicate leukemia cells and obtained a satisfied therapeutic outcomes in vivo. CONCLUSIONS: Our results suggest that the used dose of ATO may determine the fate of cell differentiation senescence or malignant transformation, and the optimal dose of ATO induced opposite efficacy in autophagy between K562 cells and their initiating cells and ultimately leads both cells to late-phase senescence.
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Antineoplásicos/administração & dosagem , Arsenicais/administração & dosagem , Leucemia Mieloide/tratamento farmacológico , Óxidos/administração & dosagem , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Arsenicais/farmacologia , Arsenicais/uso terapêutico , Autofagia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Feminino , Humanos , Células K562 , Leucemia Mieloide/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Óxidos/farmacologia , Óxidos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Carga Tumoral/efeitos dos fármacosRESUMO
Obesity is a risk factor for cancer and cancer-related mortality, however, its role in lung cancer progression remains controversial. This study aimed to assess whether high-fat diet (HFD)-induced obesity promotes lung cancer progression and whether the promotion can be decreased by Kanglaite injection (KLTI). In vivo, HFD-induced overweight or obesity increases the lung carcinoma incidence and multiplicity in a urethane-induced lung carcinogenic model and cancer-related mortality in a LLC allograft model by increasing oxidative stress and cellular signaling molecules including JAK, STAT3, Akt, mTOR, NF-κB and cyclin D1. These changes resulted in increases in vascular disruption and the lung water content, thereby promoting lung epithelial proliferation and the epithelial-mesenchymal transition (EMT) during carcinogenesis. Chronic KLTI treatment substantially prevented the weight gain resulting from HFD consumption, thereby reversing the metabolic dysfunction-related physiological changes and reducing susceptibility to lung carcinogenesis. In vitro, KLTI significantly suppressed the proliferation and induced apoptosis and differentiation in 3T3-L1 preadipocyte cells and attenuated endothelial cell permeability in HUVECs. Our study indicates that there is a potential relationship between obesity and lung cancer. This is the first study to show that obesity can directly accelerate carcinogen-induced lung cancer progression and that KLTI can decrease the lung cancer-promoting effect of HFD-induced obesity.
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Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Obesidade/complicações , Células 3T3 , Células 3T3-L1 , Adipócitos/citologia , Administração Oral , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Teste de Tolerância a Glucose , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/complicações , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Sobrepeso , Estresse Oxidativo , Fatores de Risco , Transdução de SinaisRESUMO
Urethane is a recognized genotoxic carcinogen in fermented foods and beverages. This study is to compare susceptibility of ICR mice, BALB/c mice and C57BL/6 mice to urethane-induced lung carcinogenesis. The mice were injected intraperitoneally with 600 mg/kg of urethane for three times or ten times at 7-day intervals. At week 26, lung carcinogenic incidence was found in 40% ICR mice, 20% BALB/c mice and 10% C57BL/6 mice of the 3× injection group, respectively, whereas 100% lung tumor incidence took place in three mouse strains of the 10× injection group. In the 10× injection group, urethane induced lasting glycolytic stress of lung with an increase in lactate, monocarboxylate transporter 1 (MCT-1), reactive oxygen species(ROS) and 7,8-dihydro-8-oxo-29-deoxyguanosine (8-OHdG) and a decrease in pyruvate dehydrogenase (PDH) and cytochrome C oxidase (COX). In the 3× injection group, urethane also promoted lung glycolytic stress at the end of urethane injection but it lasted no more than 7 days besides in lung tumor-bearing mice. Metformin as a glycolytic enhancer promoted urethane carcinogenic efficacy in the 3× injection group, whereas 2-deoxy-glucose (2-DG) as a glycolytic inhibitor decreased urethane carcinogenic efficacy in the 10× injection group. Further, urethane promoted tumor survival in A549 cells by inducing cancer stem-like cellular state. These data suggest that lasting glycolytic stress is sufficient for urethane-induced lung tumorigenesis, and that urethane 10× injection-induced lung cancer can serve as a valuable model for lung tumor biology and tumor prevention.
Assuntos
Carcinogênese/patologia , Glicólise/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Estresse Fisiológico/efeitos dos fármacos , Uretana/toxicidade , Animais , Carcinogênese/induzido quimicamente , Carcinógenos/toxicidade , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Desoxiglucose/farmacologia , Modelos Animais de Doenças , Suscetibilidade a Doenças/induzido quimicamente , Suscetibilidade a Doenças/patologia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Ácido Láctico/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Neoplasias Pulmonares/induzido quimicamente , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Transportadores de Ácidos Monocarboxílicos/metabolismo , Complexos Multienzimáticos/metabolismo , NADH NADPH Oxirredutases/metabolismo , Ácido Pirúvico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Simportadores/metabolismoRESUMO
Angiogenesis is necessary for cancer progression, but antiangiogenic therapy actually promotes tumor recurrence, progression, and metastasis. This study focused on the contribution of the tumor interstitial fluid (TIF) to lung cancer progression. TIF was isolated and quantified for 10 µg protein/mL. Malignant driver characteristics of TIF were examined by tumor-initiating cells (TIC), self-renewal, epithelial-mesenchymal transition (EMT), autophagy, and apoptosis in vitro. In vivo tumor model was used to investigate the mechanistic roles of TIF in lung cancer progression. In vitro, TIF exhibited distinct malignant driver characteristics, which led to increased numbers of TICs, increased self-renewal and EMT, as well as to decreased autophagy and apoptosis under cell starvation conditions. In vivo, the contribution of TIF was similar, as judged by increased TICs indicated by the cancer stem cell marker Nanog, the proliferation marker proliferating cell nuclear antigen, and the EMT marker N-cadherin; TIF also increased the formation of pulmonary tumors. Interestingly, the blockers of inflammation, Na-K-ATPase, and aldosterone receptor decreased TIF-induced tumor progression but increased angiogenesis. Further, we found that the water content of the tissue was positively correlated with the levels of plasma 5-hydroxyindoleacetic acid or tissue aquaporin-1 but not with CD31. However, vadimezan reduced angiogenesis but promoted TIF-induced tumor progression. Our results suggested that TIF could provide better nutrition to the tumor than angiogenesis and that it could promote the development of malignant phenotypes of lung cancer independently of angiogenesis.
Assuntos
Líquido Extracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neovascularização Patológica , Animais , Apoptose , Aquaporina 1/metabolismo , Autofagia , Carcinoma Pulmonar de Lewis/metabolismo , Movimento Celular , Proliferação de Células , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Humanos , Ácido Hidroxi-Indolacético/química , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica , Metástase Neoplásica , Células-Tronco Neoplásicas/patologia , Fenótipo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Cicatrização , Xantonas/químicaRESUMO
BACKGROUND: The aim of this study was to investigate the effects of arginine in the development of atherosclerosis in rats fed a high-fat diet supplemented with arginine and to evaluate the role of CD36 in this process. MATERIAL AND METHODS: A total of 40 Sprague-Dawley rats were randomly assigned to 4 groups: control group, fat diet group, simvastatin group, and arginine group. They were fed for 12 weeks and were then sacrificed. Immunohistochemical CD36 expression and pathology was investigated in the aorta; CD36 expression in mononuclear cells was detected by Western blot and RT-PCR. RESULTS: The thickness of the aortal intima, media, and I/M significantly decreased in the arginine group rats compared with those in the fat diet group (P<0.05). CD36 expression was up-regulated in rats in the fat diet group compared with the control group and was down-regulated in rats in the arginine group compared with rats in the fat diet group. CONCLUSIONS: The addition of arginine has a significant effect on reducing rat atherosclerosis development, which may be attributed to both the down-regulation of CD36 expression in rat aortic endothelial and blood mononuclear cells and the NO pathway.
Assuntos
Arginina/farmacologia , Aterosclerose/prevenção & controle , Antígenos CD36/metabolismo , Dieta Hiperlipídica/efeitos adversos , Animais , Aorta/patologia , Arginina/administração & dosagem , Western Blotting , Suplementos Nutricionais , Feminino , Imuno-Histoquímica , Masculino , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas , Túnica Íntima/patologiaRESUMO
The aim of this study is to investigate the effect of erythropoietin (EPO) gene overexpression on proliferation and migration of mouse bone marrow-derived mesenchymal stem cells (MSCs), and to determine the underlying signaling pathway. Mouse MSCs were cultured in vitro and EPO gene was transfected into the 6th generation of MSCs via lentivirus vector. The transfected cells were identified by flow cytometry and the EPO levels in supernatant were measured with ELISA. In addition, cell proliferation was assessed by CCK-8 assay and cell migration was evaluated by Transwell assay. The activation of Akt, ERK1/2, and p38MAPK signaling was detected by western blotting. The lentivirus vector containing EPO was successfully constructed and transfected into MSCs. No remarkable change was found in the cell surface markers after transfection while a significant increase of EPO level in supernatant was noticed in transfected MSCs compared to controls (P < 0.01). In addition, transfected MSCs showed a significantly enhanced proliferation (P < 0.01) as well as a notable increase in migration (P < 0.01) compared to controls. Furthermore, we also found that EPO modification enhanced the phosphorylation of PI3K/Akt and ERK signaling pathway, and suppressed the phosphorylation of p38MAPK without affecting the levels of total Akt, ERK1/2, and p38MAPK in MSCs. After transfection, MSCs secreted more EPO which enhanced the capability of proliferation and migration. Moreover, our results suggested that the enhanced proliferation and migration might be associated with activation of PI3K/Akt and ERK or inhibition of P38MAPK signaling pathway.
Assuntos
Movimento Celular/ética , Eritropoetina/genética , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Animais , Proliferação de Células/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica , Camundongos , Fosforilação/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Transfecção , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Mitochondrial dysfunction is an important factor as genetic change in controlling the growth of tumors. The current study explored whether mitochondrial dysfunction correlated with urethane-induced lung carcinogenesis in BALB/c and C57BL/6 mice that were given single- or multi-dose intraperitoneal injections of urethane. We found that mice susceptible to lung tumor formation displayed a rapid increase in the respiratory control ratio in lung mitochondria after urethane exposure, whereas resistant mice that failed to develop lung tumors maintained the same respiratory control ratio as normal, untreated mice. Furthermore, repeated urethane administration or continuous 2,4-dinitrophenol (an uncoupling agent of oxidative phosphorylation) treatment, following a single urethane exposure, could overcome resistance to carcinogenesis. In contrast, multi-dose urethane-treated mice that received genipin (a highly selective inhibitor of uncoupling protein 2) following their first dose of urethane showed a lower tumor incidence. In addition, a higher uncoupling protein 2 level and a lower complex IV level in the lungs correlated with subsequent tumor formation in BALB/c and C57BL/6 mice. In vitro, urethane suppressed cell proliferation and induced soft-agar colonies in parental L929 cells with complete mitochondrial DNA but not in ρ° L929 cells lacking mitochondrial DNA. These studies suggest that abrogation of mitochondrial is essential during urethane induced lung carcinogenesis and that uncoupling inhibition can reverse cancer morphogenesis, thus presenting an appealing method to prevent lung carcinogenesis.