RESUMEN
Serotonin (5-HT) is an essential inhibitory neurotransmitter in vivo that is critical for interneuronal communication of the nervous system. Herein, we constructed an electrochemical cell-sensing platform for 5-HT detection based on MXene/single-walled carbon nanotubes (SWCNTs) nanocomposite. The one-dimensional SWCNTs with good electrical conductivity are uniformly dispersed on the surface and intermediate layers of the two-dimensional MXene to form a tightly heterogeneous heterostructure. The synthesized MXene-SWCNTs could improve the stacking problem of MXene nanosheets and expose more active sites, effectively promoting the conductive properties and electrochemical activity of the composite. The fabricated MXene-SWCNTs/GCE possessed outstanding detection capability for 5-HT with a wide linear range of 4 nM-103.2 µM and a low detection limit of 1.5 nM. Moreover, the sensor was further applied for the real-time monitoring trace amount of 5-HT releasing from different cell lines, which confirmed its promising applications in 5-HT related physiological and pathological fields. MXene-SWCNTs/GCE was developed and applied for the real-time monitoring of trace amounts of 5-HT secreted from living cells.
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Nanotubos de Carbono , Nanotubos de Carbono/química , Serotonina , Técnicas Electroquímicas/métodos , Límite de Detección , ElectrodosRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a common cause of cancer mortality worldwide. Recent studies have shown that the polytopic enzyme membrane associated ring-CH-type finger 6 (MARCH6) participates in tumorigenesis, but its function in HCC development needs to be investigated. This study aimed to explore the role of MARCH6 in HCC. METHODS: Expression of MARCH6 in human HCC samples was checked by immunohistochemical staining assay. Clinical relevance of MARCH6 and activating transcription factor 2 (ATF2) was analyzed from TCGA database. CCK-8, EdU staining, colony formation and transwell were performed to assess cell proliferation, growth and migration. Xenografted tumorigenesis was used to examine in vivo role MARCH6. Immunoblotting was applied to detect protein abundance. RESULTS: We found that MARCH6 expression was elevated in human HCC samples. Over-expression of MARCH6 was associated with poor prognosis of HCC patients. Up-expression of MARCH6 promoted cell growth and migration of HCC cells. In contrast, the HCC cell growth and migration were suppressed by MARCH6 knockdown. Furthermore, the DNA synthesis was enhanced by MARCH6. The expression of ATF2 was potentiated by MARCH6 over-expression, while it was suppressed by MARCH6 silencing. TCGA database showed positive correlation between the expression of MARCH6 and ATF2. Importantly, ATF2 expression contributed to the oncogenic function of HCC cells. CONCLUSION: Our findings suggest that MARCH6-mediated ATF2 up-regulation contributes to HCC development. MARCH6 may be a promising target for the diagnosis and treatment of HCC.
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Factor de Transcripción Activador 2/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de la Membrana/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Factor de Transcripción Activador 2/genética , Animales , Carcinoma Hepatocelular/patología , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Femenino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Proteínas de la Membrana/genética , Ratones , Ratones Desnudos , Ubiquitina-Proteína Ligasas/genética , Regulación hacia ArribaRESUMEN
Breast cancer (BC) occurrence and development tremendously affect female health. Currently breast cancer targeted drugs are still scarce. Natural products have become the main source of targeted drug for breast cancer due to low toxicity and high efficiency. Cimigenoside, natural compound isolated and purified from Cimicifuga dahurica (Turcz.) Maxim has been suggested to utilize for breast cancer treatment, however the mechanism of action has not been elucidated yet. In this article, the antitumor potential of Cimigenoside against breast cancer in vitro and in vivo study. Moreover, we further predicted the possible binding mode of Cimigenoside with γ-secretase through molecular docking studies. The results show that Cimigenoside has a significant inhibitory effect towards the proliferation or metastasis of breast cancer cells via suppressing the Notch signaling pathway-mediated mitochondrial apoptosis and EMT (epithelial mesenchymal transition). In terms of mechanism, Cimigenoside could inhibit the activation of PSEN-1, the catalytic subunit of γ-secretase, and also by cleaving the Notch protein mediated by PSEN-1. Overall, our findings provide scientific support to utilize Cimigenoside as an effective targeted drug for clinical treatment of BC.
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Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Receptores Notch/metabolismo , Triterpenos/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral/efectos de los fármacos , Femenino , Humanos , Células MCF-7/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación del Acoplamiento Molecular , Trasplante de Neoplasias , Triterpenos/uso terapéuticoRESUMEN
DNA methyltransferase (DNMT) participates in the transformation or progression of human cancers by mediating the hypermethylation of cancer suppressors. However, the regulatory role of DNMT in pancreatic cancer cells remains poorly understood. In the present study, we demonstrated that DNMT1 repressed the expression of microRNA 34a (miR-34a) and enhanced the activation of the Notch pathway by mediating the hypermethylation of the miR-34a promoter. In patients with pancreatic cancer, the expression levels of DNMT1 were negatively related with those of miR-34a. Mechanistically, knockdown of DNMT1 decreased the methylation of the miR-34a promoter and enhanced the expression of miR-34a to inhibit the activation of the Notch pathway. Downregulation of the Notch pathway via the DNMT1/miR-34a axis significantly enhanced the sensitivity of pancreatic cells to molecular targeting agents. Therefore, the results of our study suggest that downregulation of DNMT enhances the expression of miR-34a and may be a potential therapeutic target for pancreatic cancer.
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ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Metilación de ADN/genética , Resistencia a Antineoplásicos/genética , MicroARNs/genética , Terapia Molecular Dirigida/métodos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Anciano , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia/patología , Regiones Promotoras Genéticas , Receptores Notch , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The aim of this study was to assess the comparative efficacy and safety of combination therapy with transarterial chemoembolization (TACE) and Sorafenib for patients with advanced hepatocellular carcinoma (HCC) through a systematic review and network meta-analysis and identify the best combination of TACE and Sorafenib. We searched databases for publications prior to May 2018. The prespecified efficacy outcomes were the objective response rate, overall survival rate, and time to progression. adverse effects included dermatologic, gastrointestinal, and general disorders. Subgroup analyses, meta-regression, and a network meta-analysis regarding two types of outcomes by different chemotherapy agents in TACE (5-fluorouracil, Adriamycin, Platinum, mitomycin C, hydroxycamptothecin) were included. The study is registered with PROSPERO (CRD42018098541). For efficacy outcomes, subgroups which included 5-fluorouracil and hydroxycamptothecin ranked higher than other chemotherapy agents, while mitomycin C ranked the lowest. For advanced effects, the use of mitomycin C or 5-fluorouracil as the chemotherapy agent ranked higher, while hydroxycamptothecin ranked the lowest. Therefore, we excluded 5-Fu and Mitomycin C in subsequent studies. Additionally, in the evaluation of primary adverse effects by the network meta-analysis, Platinum ranked the highest while hydroxycamptothecin ranked the lowest. Therefore, we excluded Platinum this time. Furthermore, all types of Adriamycin are not same, and some studies included two types of Adriamycin. The network meta-analysis results showed that the TACE (hydroxycamptothecinâ¯+â¯pirarubicin) +Sorafenib arm and TACE (hydroxycamptothecinâ¯+â¯epirubicin) +Sorafenib arm had significant efficacy differences. In conclusion, for patients with advanced HCC, combination therapy with HCPT plus THP/EPI in TACE and Sorfenib may be used as a first-line treatment.
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Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/terapia , Quimioembolización Terapéutica , Neoplasias Hepáticas/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Sorafenib/uso terapéutico , Terapia Combinada , HumanosRESUMEN
Transcription factor E26 transformation specific sequence 1 (ETS-1) is a primary regulator in the metastasis of human cancer cells, especially hepatocellular carcinoma (HCC) cells; and it would affect the prognosis of HCC patients who received chemotherapies. However, the regulatory role of ETS-1 in the resistance of HCC cells to molecular-targeting agent remains poorly understood. In the present work, we demonstrate that high ETS-1 expression correlates with poor prognosis of advanced HCC patients received Sorafenib treatment. Mechanistically, ETS-1 binds to nuclear Pregnane X receptor (PXR) directly and enhances PXR's transcription factor activity, which further leads to the induction of the PXR's downstream multi-drug resistance related genes. Overexpression of ETS-1 accelerates the metabolic clearance of Sorafenib in HCC cells and leads to the better survival and faster migration of those cells. The therapeutic studies show that ETS-1 promotes the Sorafenib-resistance of HCC tumor models and ETS-1 blockade enhances the anti-tumor capacity of Sorafenib by decreasing PXR activation. Thus, our study suggests that ETS-1 could enhance the activation of PXR and be a potential therapeutic target for overcoming Sorafenib resistance in HCC treatment.
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Antineoplásicos/farmacología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Receptor X de Pregnano/fisiología , Inhibidores de Proteínas Quinasas/farmacología , Proteína Proto-Oncogénica c-ets-1/fisiología , Sorafenib/farmacología , Animales , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular , Resistencia a Antineoplásicos , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Ratones Desnudos , Inhibidores de Proteínas Quinasas/uso terapéutico , Sorafenib/uso terapéuticoRESUMEN
BACKGROUND: Kinase inhibitor sorafenib is the most widely used drug for advanced HCC clinical treatment nowadays. However, sorafenib administration is only effective for a small portion of HCC patients, and the majority develop sorafenib-resistance during treatment. Thus, it is urgent to discover the endogenous mechanism and identify new pharmaceutical targets of sorafenib-resistance. METHODS: Pregnane X receptor (PXR) was detected by immunohistochemistry and quantitative PCR. GST-pull down and LC-MS/MS was used to detect the interaction of PXR and Sorafenib. To test the properties of HCC tumor growth and metastasis, in vivo tumor explant model, FACS, trans-well assay, cell-survival inhibitory assay and Western blot were performed. In terms of mechanistic study, additional assays such as ChIP and luciferase reporter gene assay were applied. RESULTS: In the present work, we found high PXR level in clinical specimens is related to the poor prognosis of Sorafenib treated patients. By the mechanistic studies, we show that sorafenib binds to PXR and activates PXR pathway, and by which HCC cells develop sorafenib-resistance via activating. Moreover, PXR overexpression helps HCC cells to persist to sorafenib treatment. CONCLUSION: This study reports the endogenous sorafenib-resistance mechanism in HCC cells, which offers an opportunity to design new therapeutic approaches for HCC treatment. GENERAL SIGNIFICANCE: PXR mediates sorafenib-resistance in HCC cells and targeting PXR can be a useful approach to facilitate HCC treatment.
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Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Receptores de Esteroides/genética , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Ratones SCID , Niacinamida/metabolismo , Niacinamida/uso terapéutico , Compuestos de Fenilurea/metabolismo , Receptor X de Pregnano , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Interferencia de ARN , Receptores de Esteroides/metabolismo , Sorafenib , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
BACKGROUND: The rapid development of multi-drug resistance (MDR) process has hindered the effectiveness of advanced hepatocellular carcinoma (HCC) treatments. Notch-1 pathway, which mediates the stress-response, promotes cell survival, EMT (epithelial-mesenchymal transition) process and induces anti-apoptosis in cancer cells, would be a potential target for overcoming MDR process. This study investigated the potential application of rhamnetin, a specific inhibitor of Notch-1 pathway, in anti-tumor drug sensitization of HCC treatment. METHODS: The expression of miR-34a, proteins belonging to Notch-1 signaling pathway or MDR-related proteins was detected by quantitative polymerase chain reaction (qPCR) and western blot assay. To identify whether rhamnetin induces the chemotherapeutic sensitization in HCC cells, the MTT-assays, flow cytometry, soft agar, trans-well and nude mice assays were performed. RESULTS: The endogenous expression of miR-34a was significantly increased and the expression of Notch-1 and Survivin was downregulated after rhamnetin treatment. Treatment of rhamnetin also reduced the expression of MDR related proteins P-GP (P-glycoprotein) and BCRP (breast cancer resistance protein). Rhamnetin increased the susceptibility of HCC cells and especially HepG2/ADR, a MDR HCC cell line, to a small molecular kinase inhibitor sorafenib or chemotherapeutic drugs etoposide and paclitaxel. The IC(50) value of those drugs correspondingly decreased. CONCLUSIONS: Together, our findings suggest that rhamnetin treatment may attenuate the MDR process in HCC cells. These findings may contribute to more effective strategies for HCC therapy. GENERAL SIGNIFICANCE: Rhamnetin acts as a promising sensitizer to chemotherapy and may be a novel approach to overcome the MDR process of HCC.
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Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Etopósido/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Paclitaxel/farmacología , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quercetina/análogos & derivados , Animales , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones SCID , MicroARNs/genética , MicroARNs/metabolismo , Niacinamida/farmacología , Quercetina/farmacología , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/metabolismo , Transducción de Señal/efectos de los fármacos , Sorafenib , Transfección , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Patients suffering from advanced stage hepatocellular carcinoma (HCC) often exhibit a poor prognosis or dismal clinical outcomes due to ineffective chemotherapy or a multi-drug resistance (MDR) process. Thus, it is urgent to develop a new chemotherapeutic sensitivity testing system for HCC treatment. The presence study investigated the potential application of a novel chemotherapeutic sensitivity-testing system based on a collagen gel droplet embedded 3D-culture system (CD-DST). METHODS: Primary cells were separating from surgical resection specimens and then tested by CD-DST. To identify whether HCC cell lines or cells separating from clinical specimens contain MDR features, the cells were treated with an IC 50 (half maximal inhibitory concentration) or IC max (maximal inhibitory concentration) concentration of antitumor agents, e.g., 5-furuolouracil (5-FU), paclitaxel (PAC), cisplatin (CDDP), epirubicin (EPI), or oxaliplatin (L-OHP), and the inhibitory rates (IRs) were calculated. RESULTS: HepG2 cells were sensitive to 5-FU, PAC, CDDP, EPI, or L-OHP; the IC 50 value is 0.83 ± 0.45 µg/ml, 0.03 ± 0.02 µg/ml, 1.15 ± 0.75 µg/ml, 0.09 ± 0.03 µg/ml, or 1.76 ± 0.44 µg/ml, respectively. Only eight (8/26), nine (9/26), or five (5/26) patients were sensitive to the IC max concentration of CDDP, EPI, or L-OHP; whereas only three (3/26), four (4/26), or two (2/26) patients were sensitive to the IC 50 concentration of CDDP, EPI, or L-OHP. No patients were sensitive to 5-FU or PAC. CONCLUSIONS: The in vitro drug sensitivity exanimation revealed the MDR features of HCC and examined the sensitivity of HCC cells from clinical specimens to anti-tumor agents. CD-DST may be a useful method to predict the potential clinical benefits of anticancer agents for HCC patients.
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Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Técnicas de Cultivo de Célula/métodos , Neoplasias Hepáticas/tratamiento farmacológico , Adulto , Antineoplásicos/farmacología , Carcinoma Hepatocelular/patología , Supervivencia Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Cisplatino/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Epirrubicina/administración & dosificación , Epirrubicina/farmacología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacología , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/farmacología , Oxaliplatino , Paclitaxel/administración & dosificación , Paclitaxel/farmacología , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
The microRNA miR-452 has been shown to function as a tumor suppressor. However, the cellular mechanism and potential application of miR-452-mediated cancer suppression remain great unknown. This study aims to identify how miR-452 acts in regulating non-small cell lung cancer (NSCLC) proliferation and metastasis. Expression of miR-452 via adenoviral (Ad) vector inhibits the proliferation, invasion, and migration of NSCLC cells A549 or H460. Our data also shows that miR-452 down-regulates the expression of Bmi-1 as well as pro-survival or anti-apoptosis regulators Survivin, cIAP-1, and cIAP-2. By such gene interference, miR-452 modulates NSCLC cell epithelial-mesenchymal transition (EMT) and further disrupts their migration and invasion. Moreover, miR-452 blocks the activation of PI3K/AKT pathway, which is also required for EMT process. These data reveal that miR-452 treatment could be a novel target or strategy for NSCLC treatment.
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Adenoviridae/genética , Carcinoma de Pulmón de Células no Pequeñas/secundario , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Vectores Genéticos , Neoplasias Pulmonares/patología , MicroARNs/genética , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Humanos , Neoplasias Pulmonares/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/genética , TransfecciónRESUMEN
BACKGROUND: Many kidney-tonifying Chinese herbal medicines exert effects on anti-aging by comprehensive interactions of multiple targets. However, the interactions of multi-targets targeted by effective ingredients of kidney-tonifying Chinese herbal medicines are unknown. In this study, to explore the systems pharmacology mechanisms of kidney-tonifying Chinese medicines on anti-aging, we establish the molecular networks with the interactions of multi-targets, analyze bio-functions and pathways with IPA, and calculated the mutual interaction pairs of targets (target pairs) with data mining, respectively. METHODS: Kidney-tonifying Chinese medicines with anti-aging effects were screened from the Chinese Pharmacopoeia and the literatures. Target proteins of these herbal medicines were obtained from bioinformatics databases. Comparisons of molecular networks, bio-functions and pathways given by Ingenuity Pathway Analysis system showed the similarities and the differences between kidney Yin-tonifying herbal medicines and kidney Yang-tonifying herbal medicines. Target pairs with high correlation related to anti-aging were also discovered by data mining algorithm. And regulatory networks of targets were built based on the target pairs. RESULTS: Twenty-eight kidney-tonifying herbal medicines with anti-aging effects and 717 related target proteins were collected. The main bio-functions that all targets enriched in were "Cell Death and Survival", "Free Radical Scavenging" and "Cellular Movement", etc. The results of comparison analysis showed that kidney Yin-tonifying herbal medicines focused more on "Cancer related signaling", "Apoptosis related signaling" and "Cardiovascular related signaling". And kidney Yang-tonifying herbal medicines focused more on "Cellular stress and injury related signaling" and "Cellular growth, proliferation and development related signaling". Moreover, the results of regulatory network showed that the anti-aging related target pairs with high correlated degrees of Kidney Yin-tonifying herbal medicines included TNF-PTGS2, TNF-CASP3, PTGS2-CASP3, CASP3-NOS2 and TNF-NOS2, and that of kidney Yang-tonifying herbal medicines included REAL-TNF, REAL-NFKBIA, REAL-JUN, PTGS2-SOD1 and TNF-IL6. CONCLUSIONS: In this study, we achieved some important targets, target pairs and regulatory networks with bioinformatics and data mining, to discuss the systems pharmacology mechanisms of kidney-tonifying herbal medicines acting on anti-aging. Mutual target pairs related to anti-aging found in this study included TNF-PTGS2, TNF-CASP3, PTGS2-CASP3, CASP3-NOS2, TNF-NOS2, REAL-TNF, REAL-NFKBIA, REAL-JUN, PTGS2-SOD1 and TNF-IL6. Target pairs and regulatory networks of targets could reflect more potential interactions between targets and comprehensive effects on anti-aging. Compared with the existing researches, it was found that the kidney-tonifying herbal medicines may exert anti-aging effects in multiple pathways in this study.
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Envejecimiento/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Redes Reguladoras de Genes/efectos de los fármacos , Proteínas/genética , Envejecimiento/genética , Biología Computacional , Minería de Datos , Expresión Génica/efectos de los fármacos , Humanos , Plantas Medicinales/química , Proteínas/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The levels of monoamine neurotransmitters (MNTs) including dopamine (DA), adrenaline (Adr), norepinephrine (NE) and 5-hydroxytryptamine (5-HT) in cells are useful indicators to explore the pathogenesis of MNTs-related diseases such as Alzheimer's disease, Parkinson's disease and depression. Herein, we constructed a novel electrochemical sensing platform based on multi-walled carbon nanotubes (MWCNTs)-amine functionalized Zr (IV) metal-organic framework (UIO-66-NH2) nanocomposite for the detection of multiple MNTs including DA, Adr, NE and 5-HT. The synergistic effect between MWCNTs and UIO-66-NH2 endowed the nanocomposite with high specific surface area, low interface impedance and superior electrocatalytic activity, which effectively enhance the electrochemical performance of the sensor. The MWCNTs-UIO-66-NH2 nanocomposite-based sensor exhibited satisfied sensitivity for the quantitative measurement of DA, Adr, NE and 5-HT, as well as low detection limit. The outstanding biocompatibility of the constructed sensor permitted it to be successfully implemented for the real-time monitoring of DA released by PC12 and C6 cells, providing a promising strategy for clinical diagnosis of MNTs-related disorders and diseases.
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Background: As a population ages, blood pressure levels gradually increase, leading to a higher incidence of hypertension and increased cardiovascular diseases risk. This study examines factors affecting hypertension grading among centenarians in the Hainan Province. Methods: Data from 2014 to 2016 were accessed from the cross-sectional database "Hypertension Levels and Epidemiological Characteristics of the Elderly and Centenarians in Hainan province of China". This study included 690 centenarians with hypertension. Hypertension grading was the dependent variable, analyzed against independent variables including demographic information (sex, age, ethnicity, education level, marital status, cohabitation, and regional distribution), lifestyle factors (smoking, alcohol consumption, and physical activity), body mass index (BMI), and comorbid conditions (diabetes and hyperlipidemia). Logistic regression models, adjusted for these factors, were used to assess the determinants of hypertension grading among the participants. Results: Multivariate regression analysis, after adjusting for other variables, revealed significant associations between BMI, low-density lipoprotein (LDL) levels, and hypertension grades. Individuals with BMI below 18.5 kg/m 2 had a 0.614-fold lower risk of developing grade III hypertension (odds ratio [OR]: 0.614, 95% confidence interval [CI]: 0.390-0.966, p = 0.0350) and a 0.586-fold lower risk for grade II hypertension (OR: 0.586, 95% CI: 0.402-0.852, p = 0.0052). Furthermore, individuals with elevated LDL levels had a 6.087-fold greater risk of progressing from grade I to grade III hypertension (OR: 6.087, 95% CI: 1.635-22.660, p = 0.0071) and a 4.356-fold greater risk of progressing from grade II to grade III hypertension (OR: 4.356, 95% CI: 1.052-18.033, p = 0.0423). Additionally, individuals of Li ethnicity had 1.823-fold greater risk of progressing from grade I to grade II hypertension compared to those of Han ethnicity (OR: 1.823, 95% CI: 1.033-3.218, p = 0.0383). Conclusions: A BMI below 18.5 kg/m 2 , elevated LDL, and ethnicity emerged the primary factors associated with hypertension grading in centenarians. To reduce the risk of hypertension, it is crucial for centenarians to maintain a healthy weight, normal LDL levels, and adopt dietary habits including a low-cholesterol and low-fat diet.
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Ferroptosis has been characterized as non-apoptotic programmed cell death and is considered a novel strategy for antitumor treatment. The factor that binds to inducer of short transcripts-1 (FBI-1) is an important proto-oncogene playing multiple roles in human malignancies and the development of resistance to therapy. However, the roles of FBI-1 in ferroptosis of endocrine independent prostate carcinoma are still unknown. The results of this study showed that FBI-1 inhibited the ferroptosis of prostate carcinoma PC-3 cells (a typical endocrine-independent prostate carcinoma cell line) via the miR-324-3p/glutathione peroxidase 4 (miR-324-3p/GPX4) axis. Overexpression of FBI-1 enhanced the expression levels of GPX4. In contrast, knockdown of FBI-1 decreased the expression of GPX4 and induced the ferroptosis of PC-3 cells. The miR-324-3p decreased the expression of GPX4 by targeting the 3'-untranslated region of GPX4 to induce ferroptosis. Notably, FBI-1 increased the expression of GPX4 by repressing the levels of miR-324-3p. The transcription of miR-324-3p was mediated by specificity protein 1 (SP1), and FBI-1 repressed the expression of miR-324-3p by repressing the activation of SP1. In clinical specimens, the endogenous levels of FBI-1 were positively associated with Glutathione Peroxidase 4 (GPX4) and negatively related with the expression of miR-324-3p. Therefore, the results indicated that the miR-324-3p/GPX4 axis participates in the FBI-1-mediated ferroptosis of prostate carcinoma cells.
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BACKGROUND: Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness. METHODS: Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression. RESULTS: We identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment. CONCLUSIONS: Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.
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Neoplasias Hematológicas , Humanos , Animales , Línea Celular Tumoral , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/metabolismo , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteolisis/efectos de los fármacos , Ubiquitina-Proteína Ligasas/metabolismo , Factor de Transcripción Ikaros/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas Adaptadoras Transductoras de SeñalesRESUMEN
Highly sensitive and specific detection and monitoring of trace norepinephrine (NE) in biological fluids and neuronal cell lines is essential for the investigation of pathogenesis of certain neurological diseases. Herein, we constructed a novel electrochemical sensor for real-time monitoring of NE released by PC12 cells based on glassy carbon electrode (GCE) modified with honeycomb-like nickel oxide (NiO)-reduced graphene oxide (RGO) nanocomposite. The synthesized NiO, RGO and the NiO-RGO nanocomposite were characterized using X-ray diffraction spectrogram (XRD), Raman spectroscopy and scanning electron microscopy (SEM). The porous three-dimensional honeycomb-like structure of NiO and high charge transfer kinetics of RGO endowed the nanocomposite with excellent electrocatalytic activity, large surface area and good conductivity. The developed sensor exhibited superior sensitivity and specificity towards NE in a wide linear range from 20 nM to 14 µM and 14 µM-80 µM, with a low detection limit of 5 nM. The performances of the sensor in terms of excellent biocompatibility and high sensitivity allow it to be successfully employed in the tracking of NE release from PC12 cells under the stimulation of K+, providing an effective strategy for the real-time monitoring of cellular NE.
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Grafito , Norepinefrina , Grafito/química , Carbono/químicaRESUMEN
Ferroptosis, a nonapoptotic form of programmed cell death characterized by significant iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various cancer-related signaling pathways. Recently, considerable progress has been made in demonstrating the critical role of lipid metabolism in regulating ferroptosis, indicating the potential of combinational strategies for treating cancer in the future. In this study, we explored the combinational effects of lipid metabolism compounds and ferroptosis inducers on renal cell carcinoma (RCC) cells. We found potent synergy of the fatty acid amide hydrolase (FAAH) inhibitor URB597 with ferroptosis inducer (1S, 3R)-RSL3 (RSL3) in inhibiting the growth and metastasis of RCC cells both in vitro and in vivo via induction of G1 cell cycle arrest and promotion of the production of lipid peroxides, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and cytosolic reactive oxygen species (ROS). In addition, inhibition of FAAH increased the sensitivity of RCC cells to ferroptosis. Genome-wide RNA sequencing indicated that the combination of URB597 and RSL3 has more significant effects on regulation of the expression of genes related to cell proliferation, the cell cycle, cell migration and invasion, and ferroptosis than either single agent alone. Moreover, we found that combinational treatment modulated the sensitivity of RCC cells to ferroptosis via the phosphatidylinositol 3 kinase (PI3K)-AKT signaling pathway. These data demonstrate that dual targeting of FAAH and ferroptosis could be a promising strategy for treating RCC.
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Carcinoma de Células Renales , Ferroptosis , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Transducción de Señal , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Renales/tratamiento farmacológicoRESUMEN
Many infection control measures have been implemented to prevent the spread of SARS-CoV-2 during COVID-19 pandemic. We aimed to investigate the impact of COVID-19 epidemic on the other notifiable infectious diseases in China, including respiratory infectious diseases, diseases transmitted through the digestive tract and animal-borne diseases. Compared with 2019, the overall decline rate of respiratory infectious diseases in 2020 is the highest (60-90%), and the diseases transmitted by the digestive tract and animal-borne diseases are similar at 20-30%. Both hepatitis and sexually transmitted diseases decreased significantly in February, and there were basically no significant changes in other months compared with previous years. The series of measures taken by China government to prevent the spread of SARS-CoV-2 are also very effective in preventing the spread of respiratory infectious diseases. But they also have a certain degree of prevention against notifiable infectious diseases spread by other routes.
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COVID-19 , Enfermedades Transmisibles , Animales , China/epidemiología , Enfermedades Transmisibles/epidemiología , Humanos , Incidencia , Pandemias , SARS-CoV-2RESUMEN
The protein kinase, TANK-binding kinase 1 (TBK1), not only regulates various biological processes but also functions as an important regulator of human oncogenesis. However, the detailed function and molecular mechanisms of TBK1 in hepatocellular carcinoma (HCC), especially the resistance of HCC cells to molecular-targeted drugs, are almost unknown. In the present work, the role of TBK1 in regulating the sensitivity of HCC cells to molecular-targeted drugs was measured by multiple assays. The high expression of TBK1 was identified in HCC clinical specimens compared with paired non-tumor tissues. The high level of TBK1 in advanced HCC was associated with a poor prognosis in patients with advanced HCC who received the molecular-targeted drug, sorafenib, compared to patients with advanced HCC patients and a low level of TBK1. Overexpression of TBK1 in HCC cells induced their resistance to molecular-targeted drugs, whereas knockdown of TBK1 enhanced the cells' sensitivity to molecular-targeted dugs. Regarding the mechanism, although overexpression of TBK1 enhanced expression levels of drug-resistance and pro-survival-/anti-apoptosis-related factors, knockdown of TBK1 repressed the expression of these factors in HCC cells. Therefore, TBK1 is a promising therapeutic target for HCC treatment and knockdown of TBK1 enhanced sensitivity of HCC cells to molecular-targeted drugs.
RESUMEN
New strategies for molecular-targeted drug therapy for advanced hepatocellular carcinoma (HCC) ignore the contribution of the nutritional status of patients and nutritional support to improve physical status and immunity. We aimed to elucidate the role of a single nucleotide mixture (SNM) in the anti-tumor therapy of HCC, and to explore the importance of a SNM as adjuvant therapy for HCC. Compared with a lipid emulsion (commonly used nutritional supplement for HCC patients), the SNM could not induce metabolic abnormalities in HCC cells (Warburg effect), and did not affect expression of metabolic abnormality-related factors in HCC cells. The SNM could also attenuate the lymphocyte injury induced by antitumor drugs in vitro and in vivo, and promote the recruitment and survival of lymphocytes in HCC tissues. Using HCC models in SCID (server combined immune-deficiency) mice or BalB/c mice, the SNM had anti-tumor activity, and could significantly upregulate the antitumor activity of molecular-targeted drugs (tyrosine-kinase inhibitors [TKI] and immune-checkpoint inhibitors [ICI]) against HCC. We employed research models in vivo and in vitro to reveal the anti-tumor activity of the SNM on HCC. Our findings expand understanding of the SNM and contribute to HCC (especially nutritional support) therapy.