RESUMEN
BACKGROUND: Radiotherapy is a highly effective treatment for cervical cancer. Recent studies focused on the radiotherapy induced anti-tumor immunity. Whether tumor-derived extracellular vesicles (EVs) play roles in radiotherapy induced tumor associated macrophage (TAM) polarization remains unclear. MATERIALS AND METHODS: This study analysed the phenotype of macrophages in cancer tissue and peripheral blood of cervical cancer patients using flow cytometry analysis. The role of EVs from plasma of post-irradiated patients on M2-like transformed macrophages was assessed. The M1- and M2-like macrophages were assessed by expression of cell surface markers (CCR7, CD163) and intracellular cytokines (IL-10, TNFα and iNOS). The capacity of phagocytosis was assessed by PD-1 expression and phagocytosis of pHrodo Red E. coli bioparticles. RESULTS: Our results demonstrated that radiotherapy of cervical cancer induced an increase in the number of TAMs and a change in their subtype from the M2-like to the M1-like phenotype (increased expression of CCR7 and decreased expression of CD163). The EVs from plasma of post-irradiated patients facilitated the M2-like to the M1-like phenotype transition (increased expression of CCR7, TNFα and iNOS, and decreased expression of CD163 and IL-10) and increased capacity of phagocytosis (decreased PD-1 expression and increased phagocytosis of pHrodo Red E. coli bioparticles). CONCLUSIONS: Our data demonstrated that irradiation in cervical cancer patients facilitated a proinflammatory macrophage phenotype which could eventually able to mediate anti-tumor immune responses. Our findings highlight the importance of EV in the crosstalk of tumor cells and TAM upon irradiation, which potentially leading to an increased inflammatory response to cancer lesions.
Asunto(s)
Anticuerpos Antineoplásicos/efectos de la radiación , Vesículas Extracelulares/efectos de la radiación , Inmunidad/efectos de la radiación , Macrófagos Asociados a Tumores/efectos de la radiación , Neoplasias del Cuello Uterino/radioterapia , Adulto , Braquiterapia , Citocinas/efectos de la radiación , Femenino , Humanos , Persona de Mediana Edad , Fenotipo , Neoplasias del Cuello Uterino/inmunologíaRESUMEN
Ovarian cancer is a gynecological malignant tumor with the highest mortality rate, and chemotherapy resistance seriously affects patient therapeutic outcomes. It has been shown that the high expression of antiapoptotic proteins Bcl2 and BclxL is closely related to ovarian cancer chemotherapy resistance. Therefore, reducing Bcl2 and BclxL expression levels may be essential for reversing drug resistance in ovarian cancer. ABT737 is a BH3only protein mimetic, which can effectively inhibit the expression of the antiapoptotic proteins BclxL and Bcl2. Although it has been shown that ABT737 can increase the sensitivity of ovarian cancer cells to cisplatin, the specific molecular mechanism remains unclear and requires further investigation. In the present study, the results revealed that ABT737 can significantly increase the activation levels of JNK and ASK1 induced by cisplatin in A2780/DDP cells, which are cisplatinresistant ovarian cancer cells. Inhibition of the JNK and ASK1 pathway could significantly reduce cisplatin cytotoxicity increased by ABT737 in A2780/DDP cells, while inhibiting the ASK1 pathway could reduce JNK activation. In addition, it was further determined that ABT737 could increase reactive oxygen species (ROS) levels in A2780/DDP cells induced by cisplatin. Furthermore, the inhibition of ROS could significantly reduce JNK and ASK1 activation and ABT737mediated increased cisplatin cytotoxicity in A2780/DDP cells. Overall, the current data identified that activation of the ROSASK1JNK signaling axis plays an essential role in the ability of ABT737 to increase cisplatin sensitivity in A2780/DDP cells. Therefore, upregulation the ROSASK1JNK signaling axis is a potentially novel molecular mechanism by which ABT737 can enhance cisplatin sensitivity of ovarian cancer cells. In addition, the present research can also provide new therapeutic strategies and new therapeutic targets for patients with cisplatinresistant ovarian cancer with high Bcl2/BclxL expression patterns.
Asunto(s)
Compuestos de Bifenilo , Cisplatino , Resistencia a Antineoplásicos , MAP Quinasa Quinasa Quinasa 5 , Sistema de Señalización de MAP Quinasas , Nitrofenoles , Neoplasias Ováricas , Piperazinas , Especies Reactivas de Oxígeno , Sulfonamidas , Humanos , Cisplatino/farmacología , Femenino , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Especies Reactivas de Oxígeno/metabolismo , MAP Quinasa Quinasa Quinasa 5/metabolismo , Compuestos de Bifenilo/farmacología , Línea Celular Tumoral , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sulfonamidas/farmacología , Nitrofenoles/farmacología , Piperazinas/farmacología , Apoptosis/efectos de los fármacos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antineoplásicos/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismoRESUMEN
Starvation therapy has shown promise as a cancer treatment, but its efficacy is often limited when used alone. In this work, a multifunctional nanoscale cascade enzyme system, named CaCO3@MnO2-NH2@GOx@PVP (CMGP), was fabricated for enhanced starvation/chemodynamic combination cancer therapy. CMGP is composed of CaCO3 nanoparticles wrapped in a MnO2 shell, with glucose oxidase (GOx) adsorbed and modified with polyvinylpyrrolidone (PVP). MnO2 decomposes H2O2 in cancer cells into O2, which enhances the efficiency of GOx-mediated starvation therapy. CaCO3 can be decomposed in the acidic cancer cell environment, causing Ca2+ overload in cancer cells and inhibiting mitochondrial metabolism. This synergizes with GOx to achieve more efficient starvation therapy. Additionally, the H2O2 and gluconic acid produced during glucose consumption by GOx are utilized by MnO2 with catalase-like activity to enhance O2 production and Mn2+ release. This process accelerates glucose consumption, reactive oxygen species (ROS) generation, and CaCO3 decomposition, promoting the Ca2+ release. CMGP can alleviate tumor hypoxia by cycling the enzymatic cascade reaction, which increases enzyme activity and combines with Ca2+ overload to achieve enhanced combined starvation/chemodynamic therapy. In vitro and in vivo studies demonstrate that CMGP has effective anticancer abilities and good biosafety. It represents a new strategy with great potential for combined cancer therapy.
Asunto(s)
Carbonato de Calcio , Glucosa Oxidasa , Compuestos de Manganeso , Óxidos , Glucosa Oxidasa/metabolismo , Glucosa Oxidasa/química , Glucosa Oxidasa/farmacología , Compuestos de Manganeso/química , Compuestos de Manganeso/farmacología , Óxidos/química , Óxidos/farmacología , Humanos , Animales , Carbonato de Calcio/química , Carbonato de Calcio/farmacología , Carbonato de Calcio/metabolismo , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Nanopartículas/química , Povidona/química , Povidona/farmacología , Hipoxia Tumoral/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Supervivencia Celular/efectos de los fármacos , Tamaño de la Partícula , Línea Celular Tumoral , Peróxido de Hidrógeno/metabolismo , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Propiedades de Superficie , Ratones Endogámicos BALB CRESUMEN
Inorganic mercury (IHg) is hazardous to marine organisms especially resulting in neurotoxicity, bivalves are sensitive to pollutants as "ocean sentinel", but data on the neurotoxicity of IHg in bivalves are sparse. So we chosed M. chinensis philippi with typical neural structures in bivalves to investigate the neurotoxicity of IHg, which could be helpful to understand the specificity of neural regulation and the response characteristics of bivalves. After acute exposed to IHg (HgCl2) for 24 h, the metabolites of ganglion tissues in M. chinensis philippi were evaluated using 1H-nuclear magnetic resonance based metabolomics; Ca2+, neurotransmitters (nitric oxide, glutamate, acetylcholine) and related enzymes (calcineurin, nitric oxide synthase and acetylcholinesterase) were measured using biochemical detection. Compared to the control group, the levels of the nitric oxide (81.04 ± 12.84 µmol/g prot) and acetylcholine (30.93 ± 12.57 µg/mg prot) in M. chinensis philippi of IHg-treated were decreased, while glutamate (2.11 ± 0.61 mmol/L) increased significantly; the activity of nitric oxide synthase (679.34 ± 135.33 U/mg prot) was increased, while acetylcholinesterase (1.39 ± 0.44 U/mg prot) decreased significantly, and the activity of calcineurin (0.52 ± 0.02 U/mg prot) had a statistically insignificant increasing tendency. The concentration of Ca2+ (0.92 ± 0.46 mmol/g prot) in the IHg-treated group was significantly higher than that in the control group. OPLS-DA was performed to reveal the difference in metabolites between the control and IHg-challenged groups, the metabolites of glucose, glutamine, inosine, succinate, glutamate, homarine, and alanine were sensitive to IHg, subsequently metabolic pathways that were affected including glucose metabolism, glutamine metabolism, nucleotide metabolism, Krebs cycle, amino acid metabolism and osmotic regulation. In our study, IHg interfered with metabolites in M. chinensis philippi, thus the corresponding metabolic pathways were changed, which influenced the neurotransmitters subsequently. Furthermore, Ca2+overload affected the synthesis or degradation of the neurotransmitters, and then the altered neurotransmitters involved in changes in metabolic pathways again. Overall, we hypothesized that the neurotoxic effects of IHg on bivalve were in close contact with metabolism, neurotransmitters, related enzymes and Ca2+, which could be effective neurotoxic biomarkers for marine environmental quality assessment, and also provide effective data for the study of the regulatory mechanism of the nervous system in response to IHg in bivalves.
Asunto(s)
Bivalvos , Mercurio , Compuestos de Metilmercurio , Contaminantes Químicos del Agua , Animales , Mercurio/toxicidad , Mercurio/metabolismo , Acetilcolinesterasa , Óxido Nítrico , Acetilcolina , Calcineurina , Glutamina , Contaminantes Químicos del Agua/toxicidad , Bivalvos/metabolismo , Glutamatos , Neurotransmisores , Óxido Nítrico Sintasa , Compuestos de Metilmercurio/toxicidadRESUMEN
Climate change affects wetland vegetation dramatically in mid- and high- latitudes, especially in the Amur River basin (ARB), straddling three countries and distributing abundance wetlands. In this study, spatiotemporal changes in average normalized difference vegetation index (NDVI) of wetland during the annual growing season were examined in the ARB from 1982 to 2020, and the responses of wetland vegetation to climatic change (temperature and precipitation) in different countries, geographic gradients, and time periods were analyzed by correlation analysis. The NDVI of wetland in the ARB increased significantly (p < 0.01) at the rate of 0.023 per decade from 1982 to 2020, and the NDVI on the Russian side (0.03 per decade) increased faster than that on the Chinese side (0.02 per decade). The NDVI of wetland was significantly positively correlated with daily mean temperature (p < 0.05, r = 0.701) and negatively correlated with precipitation, although the correlation was not significant (p > 0.05, r = -0.12). However, the asymmetric effects of diurnal warming on wetland vegetation were weak in the ARB. Correlations between the NDVI of wetland and climatic factors were zonal in latitudinal and longitudinal directions, and 49°N and 130°E were the points for a shift between increasing and decreasing correlation coefficients, closely related to the climatic zone. Under climate warming scenarios, the NDVI of wetland is predicted to continue to increase until 2080. The findings of this study are expected to deepen the understanding on response of wetland ecosystem to global change and promote regional wetland ecological protection.