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1.
Adv Sci (Weinh) ; : e2406683, 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-38984397

RESUMEN

Given that tumor microenvironment (TME) exerts adverse impact on the therapeutic response and clinical outcome, robust TME modulators may significantly improve the curative effect and increase survival benefits of cancer patients. Here, Au nanodots-anchored CoFe2O4 nanoflowers with PEGylation (CFAP) are developed to respond to TME cues, aiming to exacerbate redox dyshomeostasis for efficacious antineoplastic therapy under ultrasound (US) irradiation. After uptake by tumor cells, CFAP with glucose oxidase (GOx)-like activity can facilitate glucose depletion and promote the production of H2O2. Multivalent elements of Co(II)/Co(III) and Fe(II)/Fe(III) in CFAP display strong Fenton-like activity for·OH production from H2O2. On the other hand, energy band structure CFAP is superior for US-actuated 1O2 generation, relying on the enhanced separation and retarded recombination of e-/h+ pairs. In addition, catalase-mimic CFAP can react with cytosolic H2O2 to generate molecular oxygen, which may increase the product yields from O2-consuming reactions, such as glucose oxidation and sonosensitization processes. Besides the massive production of reactive oxygen species, CFAP is also capable of exhausting glutathione to devastate intracellular redox balance. Severe immunogenic cell death and effective inhibition of solid tumor by CFAP demonstrates the clinical potency of such heterogeneous structure and may inspire more relevant designs for disease therapy.

2.
MedComm (2020) ; 5(6): e564, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38807975

RESUMEN

Currently, tumor treatment modalities such as immunotherapy and targeted therapy have more stringent requirements for obtaining tumor growth information and require more accurate and easy-to-operate tumor information detection methods. Compared with traditional tissue biopsy, liquid biopsy is a novel, minimally invasive, real-time detection tool for detecting information directly or indirectly released by tumors in human body fluids, which is more suitable for the requirements of new tumor treatment modalities. Liquid biopsy has not been widely used in clinical practice, and there are fewer reviews of related clinical applications. This review summarizes the clinical applications of liquid biopsy components (e.g., circulating tumor cells, circulating tumor DNA, extracellular vesicles, etc.) in tumorigenesis and progression. This includes the development process and detection techniques of liquid biopsies, early screening of tumors, tumor growth detection, and guiding therapeutic strategies (liquid biopsy-based personalized medicine and prediction of treatment response). Finally, the current challenges and future directions for clinical applications of liquid biopsy are proposed. In sum, this review will inspire more researchers to use liquid biopsy technology to promote the realization of individualized therapy, improve the efficacy of tumor therapy, and provide better therapeutic options for tumor patients.

3.
Environ Toxicol ; 2024 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-38581214

RESUMEN

BACKGROUND: Protein tyrosine phosphatase non-receptor type 7 (PTPN7) is a signaling molecule that regulates a multitude of cellular processes, spanning cell proliferation, cellular differentiation, the mitotic cycle, and oncogenic metamorphosis. However, the characteristic of PTPN7 in the glioma microenvironment has yet to be elucidated. METHODS: The prognostic value, genomic features, immune characteristics, chemotherapy prediction, and immunotherapy prediction of PTPN7 were systematically explored at the bulk sequencing level. The cell evolution trajectory, cell communication pattern, and cell metabolic activity related to PTPN7 were systematically explored at the single-cell sequencing level. HMC3 and M0 cells were cocultured with U251 and T98G cells, and flow cytometry was carried out to investigate the polarization of HMC3 and M0. Transwell assay and CCK-8 assay were performed to explore the migration and proliferation activity of U251 and T98G. RESULTS: The expression level of PTPN7 is significantly elevated in glioma and indicates malignant features. PTPN7 expression predicts worse prognosis of glioma patients. PTPN7 is associated with genome alteration and immune infiltration. Besides, PTPN7 plays a crucial role in modulating metabolic and immunogenic processes, particularly by influencing the activity of microglia and macrophages through multiple signaling pathways involved in cellular communication. Specifically, PTPN7 actively mediates inflammation-resolving-polarization of macrophages and microglia and protects glioma from immune attack. PTPN7 could also predict the response of immunotherapy. CONCLUSIONS: PTPN7 is critically involved in inflammation-resolving-polarization mediated by macrophage and microglia and promotes the immune escape of glioma cells.

4.
Adv Sci (Weinh) ; 11(6): e2306190, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38049204

RESUMEN

Radiotherapy (RT) resistance is an enormous challenge in glioblastoma multiforme (GBM) treatment, which is largely associated with DNA repair, poor distribution of reactive radicals in tumors, and limited delivery of radiosensitizers to the tumor sites. Inspired by the aberrant upregulation of RAD51 (a critical protein of DNA repair), scavenger receptor B type 1 (SR-B1), and C-C motif chemokine ligand 5 (CCL5) in GBM patients, a reduction-sensitive nitric oxide (NO) donor conjugate of gemcitabine (RAD51 inhibitor) (NG) is synthesized as radio-sensitizer and a CCL5 peptide-modified bioinspired lipoprotein system of NG (C-LNG) is rationally designed, aiming to preferentially target the tumor sites and overcome the RT resistance. C-LNG can preferentially accumulate at the orthotopic GBM tumor sites with considerable intratumor permeation, responsively release the gemcitabine and NO, and then generate abundant peroxynitrite (ONOO- ) upon X-ray radiation, thereby producing a 99.64% inhibition of tumor growth and a 71.44% survival rate at 120 days in GL261-induced orthotopic GBM tumor model. Therefore, the rationally designed bioinspired lipoprotein of NG provides an essential strategy to target GBM and overcome RT resistance.


Asunto(s)
Glioblastoma , Oxadiazoles , Fármacos Sensibilizantes a Radiaciones , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Glioblastoma/genética , Gemcitabina , Línea Celular Tumoral , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Lipoproteínas
5.
Acta Biomater ; 166: 552-566, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37236575

RESUMEN

Immune checkpoint blockade (ICB) therapy has shown great potential in the treatment of malignant tumors, but its therapeutic effect on glioblastoma (GBM) is unsatisfactory because of the low immunogenicity and T cell infiltration, as well as the presence of blood-brain barrier (BBB) that blocks most of ICB agents to the GBM tissues. Herein, we developed a biomimetic nanoplatform of AMNP@CLP@CCM for GBM-targeted photothermal therapy (PTT) and ICB synergistic therapy by loading immune checkpoint inhibitor CLP002 into the allomelanin nanoparticles (AMNPs) and followed by coating cancer cell membranes (CCM). The resulting AMNP@CLP@CCM can successfully cross the BBB and deliver CLP002 to GBM tissues due to the homing effect of CCM. As a natural photothermal conversion agent, AMNPs are used for tumor PTT. The increased local temperature by PTT not only enhances BBB penetration but also upregulates the PD-L1 level on GBM cells. Importantly, PTT can effectively stimulate immunogenic cell death to induce tumor-associated antigen exposure and promote T lymphocyte infiltration, which can further amplify the antitumor immune responses of GBM cells to CLP002-mediated ICB therapy, resulting in significant growth inhibition of the orthotopic GBM. Therefore, AMNP@CLP@CCM has great potential for the treatment of orthotopic GBM by PTT and ICB synergistic therapy. STATEMENT OF SIGNIFICANCE: The effect of ICB therapy on GBM is limited by the low immunogenicity and insufficient T-cell infiltration. Here we developed a biomimetic nanoplatform of AMNP@CLP@CCM for GBM-targeted PTT and ICB synergistic therapy. In this nanoplatform, AMNPs are used as both photothermal conversion agents for PTT and nanocarriers for CLP002 delivery. PTT not only enhances BBB penetration but also upregulates the PD-L1 level on GBM cells by increasing local temperature. Additionally, PTT also induces tumor-associated antigen exposure and promotes T lymphocyte infiltration to amplify the antitumor immune responses of GBM cells to CLP002-mediated ICB therapy, resulting in significant growth inhibition of the orthotopic GBM. Thus, this nanoplatform holds great potential for orthotopic GBM treatment.


Asunto(s)
Glioblastoma , Nanopartículas , Humanos , Fototerapia/métodos , Antígeno B7-H1 , Melaninas , Glioblastoma/terapia , Glioblastoma/patología , Biomimética , Inmunoterapia , Nanopartículas/uso terapéutico , Línea Celular Tumoral
6.
Cell Death Dis ; 14(4): 235, 2023 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-37012233

RESUMEN

Exosomes, the cell-derived small extracellular vehicles, play a vital role in intracellular communication by reciprocally transporting DNA, RNA, bioactive protein, chains of glucose, and metabolites. With great potential to be developed as targeted drug carriers, cancer vaccines and noninvasive biomarkers for diagnosis, treatment response evaluation, prognosis prediction, exosomes show extensive advantages of relatively high drug loading capacity, adjustable therapeutic agents release, enhanced permeation and retention effect, striking biodegradability, excellent biocompatibility, low toxicity, etc. With the rapid progression of basic exosome research, exosome-based therapeutics are gaining increasing attention in recent years. Glioma, the standard primary central nervous system (CNS) tumor, is still up against significant challenges as current traditional therapies of surgery resection combined with radiotherapy and chemotherapy and numerous efforts into new drugs showed little clinical curative effect. The emerging immunotherapy strategy presents convincing results in many tumors and is driving researchers to exert its potential in glioma. As the crucial component of the glioma microenvironment, tumor-associated macrophages (TAMs) significantly contribute to the immunosuppressive microenvironment and strongly influence glioma progression via various signaling molecules, simultaneously providing new insight into therapeutic strategies. Exosomes would substantially assist the TAMs-centered treatment as drug delivery vehicles and liquid biopsy biomarkers. Here we review the current potential exosome-mediated immunotherapeutics targeting TAMs in glioma and conclude the recent investigation on the fundamental mechanisms of diversiform molecular signaling events by TAMs that promote glioma progression.


Asunto(s)
Exosomas , Glioma , Humanos , Macrófagos Asociados a Tumores/patología , Exosomas/metabolismo , Glioma/patología , Transducción de Señal , Biomarcadores/metabolismo , Microambiente Tumoral
7.
Stem Cells Int ; 2022: 4249843, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35966130

RESUMEN

Impairment of bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) contributes to the progression of vascular complications in subjects with diabetes. Very small amounts of bacterial-derived pathogen-associated molecular patterns (PAMPs) establish the bone marrow cell pool. We hypothesize that alteration of the PAMP peptidoglycan (PGN) exacerbates HSPC dysfunction in diabetes. We observed increased PGN infiltration in the bone marrow of diabetic mice. Exogenous administration of PGN selectively reduced the number of long-term repopulating hematopoietic stem cells (LT-HSCs), accompanied by impaired vasoreparative functions in db/db mouse bone marrow. We further revealed that bone marrow denervation contributed to PGN-associated HSPC dysfunction. Inhibition of NOD1 ameliorated PGN-induced bone marrow autonomic neuropathy, which significantly rejuvenated the HSPC pools and functions in vivo. These data reveal for the first time that PGN, as a critical factor on the gut-bone marrow axis, promotes bone marrow denervation and HSPC modulation in the context of diabetes.

8.
Trials ; 23(1): 234, 2022 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-35346332

RESUMEN

BACKGROUND: Temozolomide is applied as the standard chemotherapy agent in patients with glioblastoma (GBM) after surgery. However, the benefit of this treatment for patients is limited by the invasive growth of gliomas and drug resistance. There are indications from fundamental experimental and retrospective studies that levetiracetam has the potential to improve the survival rate of patients with GBM. However, it has yet to be determined whether the combination of temozolomide and levetiracetam is more effective than standard temozolomide chemotherapy. Therefore, we designed a randomized clinical trial to investigate the therapeutic effect of the new combined regime for treating GBM. METHODS/DESIGN: This is a double-blind and randomized clinical trial conducted in a single center. One hundred forty-two patients will be recruited and screened for the inclusion and exclusion criteria. Then, eligible participants will be randomly assigned to an experimental group or a control group in a 1:1 ratio. Based on the administration of radiation therapy (RT), participants in the experimental group will be prescribed levetiracetam plus temozolomide chemotherapy for 34 weeks while participants in the control group will receive placebo tablets plus temozolomide for the same duration. A 3-year follow-up will be conducted on all patients after intervention. Accordingly, the primary outcome will be progression-free survival (PFS). The secondary endpoints include overall survival (OS), the Karnofsky Performance Status (KPS), the objective response rate (ORR), and adverse event incidence. DISCUSSION: It is expected that the results of this trial will provide high-level evidence regarding the clinical benefits of levetiracetam and temozolomide combined in the treatment of GBM. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100049941 . Registered on 14 August 2021.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/cirugía , Glioblastoma/tratamiento farmacológico , Glioblastoma/cirugía , Humanos , Levetiracetam/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Temozolomida/efectos adversos
9.
Front Oncol ; 11: 781150, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34917508

RESUMEN

BACKGROUND: Brain metastases (BMs) are associated with poor prognosis and significant mortality, and approximately 25% of patients with non-small cell lung cancer (NSCLC) develop BMs. The present study was aimed to understand the relationships between BM and NSCLC and reveal potential biomarkers and therapeutic targets in NSCLC-related BM. METHODS: The differentially expressed genes (DEGs) expressed during NSCLC and BM development were predicted by bioinformatics analysis, and the expression of the upstream transcription factor nuclear factor of activated T cells (NFAT) was confirmed as a differential gene expressed in both NSCLC and BM. In addition, the expression of proteins encoded by these DEGs was verified by immunohistochemical experiments examining normal lung tissue, lung cancer tissue, and brain metastasis tissue from 30 patients with NSCLC related BM. RESULTS: The co-DEGs interleukin (IL)-11, cadherin 5 (CDH5) and C-C motif chemokine 2 (CCL2) link NSCLC and BM in the Gene Expression Omnibus (GEO) database, and NFAT may target the expression of these co-DEGs. In the GEO database, NFATc1 and NFATc3 were significantly downregulated in NSCLC tissues (P <.05), whereas NFATc1, NFATc2, NFATc3, and NFATc4 were significantly downregulated in BMs (P <.05). Consistent findings were observed in the immunohistochemical analysis. CONCLUSION: NFATc1 and NFATc3 may play important roles in the occurrence of NSCLC and BM by regulating IL-11, CDH5, and CCL2.

10.
Anticancer Drugs ; 30(6): 604-610, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30855310

RESUMEN

Glioma is a primary intracranial malignant tumor with poor prognosis. In this study, we aimed to develop transferrin (Tf)-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles to deliver temozolomide (TMZ) to glioma and evaluate their efficacy to kill glioma. TMZ-loaded nanoparticles were prepared by nanoprecipitation technique and targeted by Tf. Tf-PLGA-TMZ and PLGA-TMZ were characterized for average particle sizes and zeta potentials, cellular uptake and cytotoxicity as well as in-vitro drug release of these nanoparticles were evaluated in human glioma U87MG cells. In-vivo antiglioma efficacy of Tf-PLGA-TMZ was evaluated in nude mice. Polydispersity ratio increased from 0.132 to 0.150, while encapsulation efficiency decreased from 69.4 to 55.8% after Tf modification of PLGA-TMZ. High performance liquid chromatography test showed that Tf-targeted nanoparticles were better internalized into U87MG cells than nontargeted nanoparticles. Moreover, Tf-PLGA-TMZ significantly decreased the viability of U87MG cells compared with nontargeted nanoparticles (P<0.05). In addition, Tf-PLGA-TMZ significantly decreased tumor volume and improved the survival of nude mice injected with U87MG cells. Tf-modified PLGA nanoparticles could be used for effective delivery of TMZ and have promise for the treatment of glioma.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Glioma/tratamiento farmacológico , Nanopartículas/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Temozolomida/farmacología , Transferrina/química , Animales , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacología , Apoptosis , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Proliferación Celular , Portadores de Fármacos/química , Femenino , Glioma/metabolismo , Glioma/patología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Temozolomida/química , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
11.
World Neurosurg ; 129: e1-e5, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30780038

RESUMEN

BACKGROUND: Shunt-dependent hydrocephalus (SDH) is a common complication after aneurysmal subarachnoid hemorrhage and affects its outcome significantly. Whether fenestration of the lamina terminalis (FLT) during anterior circulation aneurysm clipping for aneurysmal subarachnoid hemorrhage can decrease the occurrence of SDH is still controversial. METHODS: Ovid and PubMed databases were retrieved by the following key words: "hydrocephalus," "subarachnoid hemorrhage," "aneurysm," "fenestration," and "lamina terminalis." The Cochran-Mantel-Haenszel test was used to compare overall incidence of SDH. RESULTS: The literatures were searched, and 15 were included involving 2839 patients. The overall incidence of SDH in fenestrated cohort was 11.4%, compared with 15.3% in the nonfenestrated cohort (P = 0.008). The relative risk of SDH in fenestrated cohort was 0.67 (95% confidence interval 0.50-0.90). CONCLUSIONS: This meta-analysis suggests that FLT during anterior circulation aneurysm clipping reduces the incidence of SDH. However, a well-designed, randomized controlled trial is necessary to prove the efficacy of FLT to reduce SDH.


Asunto(s)
Hidrocefalia/prevención & control , Aneurisma Intracraneal/cirugía , Complicaciones Posoperatorias/prevención & control , Hemorragia Subaracnoidea/cirugía , Humanos , Hidrocefalia/etiología , Hipotálamo/cirugía , Aneurisma Intracraneal/complicaciones , Complicaciones Posoperatorias/etiología , Hemorragia Subaracnoidea/complicaciones , Instrumentos Quirúrgicos
12.
Br J Neurosurg ; 33(2): 145-148, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30775930

RESUMEN

BACKGROUND/OBJECTIVE: Hypertensive spontaneous intracerebral hemorrhages (ICH) cause significant morbidity and mortality. In this study, we aimed to investigate the association between calcium level at admission and outcome in hypertensive ICH patients. METHODS: 658 hypertensive ICH patients were enrolled from January 2012 to January 2016 in this retrospective study, and demographic, clinical, laboratory, radiographic, and outcome data were collected. The associations between serum calcium level and initial hematoma volume, hematoma enlargement and functional outcome were assessed. RESULTS: Lower calcium level at admission was associated with larger initial hematoma volumes, baseline NIHSS and mRSscore (p < .05), but not with platelet count, activated partial thromboplastin time and international normalized ratio on admission (p > .05). For outcome assessment, 30 days mortality and 6 months mRS were adjusted for age, gender and time from onset to admission, cigarette smoking, alcohol drinking, history of hypertension, baseline NIHSS score, Baseline mRS score and hematoma position, lower calcium level at admission was associated with worse outcomes. CONCLUSION: Low calcium level at admission is associated with worse outcome and might be a prognostic factor for acute ICH.


Asunto(s)
Calcio/sangre , Hemorragia Intracraneal Hipertensiva/sangre , Hemorragia Intracraneal Hipertensiva/terapia , Factores de Edad , Anciano , Consumo de Bebidas Alcohólicas/efectos adversos , Femenino , Hematoma/diagnóstico por imagen , Humanos , Relación Normalizada Internacional , Hemorragia Intracraneal Hipertensiva/mortalidad , Masculino , Persona de Mediana Edad , Tiempo de Tromboplastina Parcial , Admisión del Paciente , Recuento de Plaquetas , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Factores Sexuales , Fumar/efectos adversos , Resultado del Tratamiento
13.
Toxicol Sci ; 144(1): 197-203, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25516494

RESUMEN

There is growing evidence that oxidative stress plays critical roles in the pathogenesis of cardiac remodeling. In the present study, we established a rat model of passive smoking and investigated the antioxidant effects of hydrogen sulfide (H2S) on smoking-induced left ventricular remodeling. Cardiac structure and function were evaluated using 2-dimensional echocardiography. Myocardial fibrosis was detected by Masson's trichrome staining and immunohistochemistry. Oxidative stress was assessed by measuring malondialdehyde levels, superoxide dismutase and glutathione peroxidase activities, and reactive oxygen species generation in the myocardium. Neonatal rat cardiomyocytes transfected with specific siRNA and exposed to cigarette smoke condensate and H2S donor sodium hydrosulfide were used to confirm the involvement of Nrf2 and PI3K/Akt signaling in the antioxidant effects of H2S. Our results indicated that H2S could protect against left ventricular remodeling in smoking rats via attenuation of oxidative stress. Moreover, H2S was also found to increase the phosphorylation of Akt and GSK3ß and decrease the nuclear expression of Fyn, which consequently leads to nuclear translocation of Nrf2 and elevated expression of HO-1 and NQO1. In conclusion, H2S may exert antioxidant effects on left ventricular remodeling in smoking rats via PI3K/Akt-dependent activation of Nrf2 signaling.


Asunto(s)
Antioxidantes/farmacología , Sulfuro de Hidrógeno/farmacología , Hipertrofia Ventricular Izquierda/prevención & control , Factor 2 Relacionado con NF-E2/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Humo/efectos adversos , Sulfuros/farmacología , Contaminación por Humo de Tabaco/efectos adversos , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Animales Recién Nacidos , Antioxidantes/metabolismo , Células Cultivadas , Citoprotección , Modelos Animales de Enfermedad , Activación Enzimática , Fibrosis , Sulfuro de Hidrógeno/metabolismo , Hipertrofia Ventricular Izquierda/enzimología , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/patología , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasa/genética , Fosforilación , Proteínas Proto-Oncogénicas c-akt/genética , Interferencia de ARN , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Sulfuros/metabolismo , Transfección
14.
World J Emerg Med ; 5(4): 298-305, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25548605

RESUMEN

BACKGROUND: Cardiac arrest (CA) is a common and serious event in emergency medicine. Despite recent improvements in resuscitation techniques, the survival rate of patients with CA is unchanged. The present study was undertaken to observe the effect of mild hypothermia (MH) on the reactive oxygen species (ROS) and the effect of neurological function and related mechanisms. METHODS: Sixty-five healthy male Sprague Dawley (SD) adult rats were randomly (random number) divided into 2 groups: blank control group (n=5) and CPR group (n=60). CA was induced by asphyxia. The surviving rats were randomly (random number) divided into two groups: normothermia CPR group (NT) and hypothermia CPR group (HT). Normothermia of 37 °C was maintained in the NT group after return of spontaneous circulation (ROSC), hypothermal intervention of 32 °C was carried out in the HT group for 4 hours immediately after ROSC. Both the NT and HT groups were then randomly divided into 2 subgroups 12 hours and 24 hours after ROSC (NT-12, NT-24, HT-12, HT-24 subgroups). During observation, the neurological deficit scores (NDSs) was recorded, then the bilateral hippocampi were obtained from rats' head, and monoplast suspension of fresh hippocampus tissue was made immediately to determine the level of intracellular ROS by flow cytometry. Transmission electron microscope was used to observe the ultramicro changes of cellular nucleus and mitochondria. Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the expression of caspase-3 mRNA, and western-blotting (WB) was used to determine the level of LC3 in frozen hippocampus tissue. Measured data were analyzed with paired sample t test and One-Way ANOVA. RESULTS: Of 60 rats with CA, 44 (73%) were successfully resuscitated and 33 (55%) survived until the end of the experiment. The NDSs of rats in the NT and HT groups were more significantly reduced than those in the BC group (F=8.107, P<0.05), whereas the NDSs of rats in the HT-12 and HT-24 subgroups were significantly increased in comparison with those NDSs of rats in the NT-12 and NT-24 subgroups, respectively (t=9.692, P<0.001; t=14.374, P<0.001). The ROS in hippocampus nerve cells in the NT and HT groups significantly increased compared to the BC group (F=16.824, P<0.05), whereas the ROS in the HT-12 and HT-24 subgroups significantly reduced compared with that ROS in the NT-12 and NT-24 subgroups, respectively (t=9.836, P<0.001; t=7.499, P<0.001). The expression of caspase-3 mRNA in hippocampus nerve cells in the NT and HT groups were significantly increased compared to the BC group (F=24.527, P<0.05), whereas the expression of caspase-3 mRNA in rats of the HT-12 and HT-24 subgroups was significantly reduced compared to the NT-12 and NT-24 subgroups, respectively (t=6.935, P<0.001; t=4.317, P<0.001). The expression of LC3B-II/I in hippocampus nerve cells of rats in the NT and HT groups significantly increased compared to the BC group (F=6.584, P<0.05), whereas the expression of LC3B-II/I in rats of the HT-12 and HT-24 subgroups significantly reduced compared to the NT-12 and NT-24 subgroups, respectively (t=10.836, P<0.001; t=2.653, P=0.02). Ultrastructure damage of nucleus and mitochondria in the NT group was more evident than in the BC group, and eumorphism of nucleus and mitochondria were maintained in rats of the HT group compared with the NT group. CONCLUSION: Mild hypothermia lessened the injury of nerve cells and improved the neurological function of rats that survived from cardiac arrest by reducing the ROS production of nerve cells and inhibiting the expression of caspase-3 mRNA and LC3, leading to cellular apoptosis and massive autophagy in rats that survived from cardiac arrest after CPR.

15.
Neurol Sci ; 35(11): 1691-9, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24816750

RESUMEN

Mild hypothermia is an effective therapeutic strategy to improve poor neurological outcomes in patients following cardiac arrest (CA). However, the underlying mechanism remains unclear. The aim of the study was to evaluate the effect of mild hypothermia on intracellular autophagy and mitophagy in hippocampal neurons in a rat model of CA. CA was induced in Sprague-Dawley (SD) rats by asphyxia for 5 min. After successful resuscitation, the surviving rats were randomly divided into two groups, the normothermia (NT) group and the hypothermia (HT) group. Mild hypothermia (32 °C) was induced following CA for 4 h, and animals were rewarmed at a rate of 0.5 °C/h. Neurologic deficit scores (NDS) were used to determine the status of neurological function. Cytoplasmic and mitochondrial protein from the hippocampus was extracted, and the expression of LC3B-II/I and Parkin were measured as markers of intracellular autophagy and mitophagy, respectively. Of the 60 rats that underwent CA, 44 were successfully resuscitated (73 %), and 33 survived until the end of the experiment (55 %). Mild hypothermia maintained eumorphism of nuclear and mitochondrial structures and significantly improved NDS (p < 0.05). Expression of LC3B-II/I and Parkin in hippocampal nerve cells were significantly increased (p < 0.05) in the NT group relative to the control. Meanwhile, mild hypothermia reduced the level of LC3B-II/I and Parkin (p < 0.05) relative to the NT group. Mild hypothermia protected mitochondria and improved neurological function following CA and resuscitation after ischemia/reperfusion (I/R) injury, likely by reducing excessive autophagy and mitophagy in neurons.


Asunto(s)
Autofagia/fisiología , Paro Cardíaco/fisiopatología , Hipocampo/patología , Hipotermia Inducida , Mitofagia/fisiología , Animales , Asfixia/complicaciones , Western Blotting , Modelos Animales de Enfermedad , Paro Cardíaco/etiología , Masculino , Microscopía Electrónica de Transmisión , Proteínas Asociadas a Microtúbulos/biosíntesis , Ratas , Ratas Sprague-Dawley , Ubiquitina-Proteína Ligasas/biosíntesis
16.
ACS Appl Mater Interfaces ; 5(15): 6909-14, 2013 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-23883622

RESUMEN

Transferrin (Tf), an iron-transporting serum glycoprotein that binds to receptors overexpressed at the surface of glioma cells, was chosen as the ligand to develop Tf-conjugated PEGylated nanoscaled graphene oxide (GO) for loading and glioma targeting delivery of anticancer drug doxorubicin (Dox) (Tf-PEG-GO-Dox). Tf-GO with lateral dimensions of 100-400 nm exhibited a Dox loading ratio up to 115.4%. Compared with Dox-loaded PEGylated GO (PEG-GO-Dox) and free Dox, Tf-PEG-GO-Dox displayed greater intracellular delivery efficiency and stronger cytotoxicity against C6 glioma cells. A competition test showed that Tf was essential to glioma targeting in vitro. The HPLC assay for Dox concentration in tumor tissue and contrapart tissue of the brain demonstrated that Tf-PEG-GO-Dox could deliver more Dox into tumor in vivo. The life span of tumor bearing rats after the administration of Tf-PEG-GO-Dox was extended significantly compared to the rats treated with saline, Dox, and PEG-GO-Dox. In conclusion, we developed Tf-PEG-GO-Dox which exhibited significantly improved therapeutic efficacy for glioma both in vitro and in vivo.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Glioma/tratamiento farmacológico , Grafito/química , Óxidos/química , Transferrina/química , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Unión Competitiva , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Glioma/metabolismo , Masculino , Nanoestructuras , Nanotecnología/métodos , Trasplante de Neoplasias , Ratas , Ratas Sprague-Dawley , Distribución Tisular
17.
Cancer Biother Radiopharm ; 28(9): 691-6, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23786401

RESUMEN

Doxorubicin (Dox) is widely used for the treatment of solid tumors but its clinical utility on glioma is limited. In this study, we developed a novel nano-scale drug delivery system employing biodegradable nanoparticle (NP) as carriers to load Dox. Transferrin (Tf) was conjugated to the surface of NP to specifically target the NP to glioma. Tf-NP-Dox was prepared via emulsification-solvent evaporation method, and characterized for the size, Drug loading capacity (DLC), entrapment efficiency, and Tf number on the surface. The antitumor efficiency in vitro was evaluated via CCK-8 assay. The transmembrane transportation was evaluated via HPLC assay. The antitumor efficiency in vivo was assessed in C6 glioma intracranial implant rat model. The average diameter of Tf-NP-Dox was 100 nm with ∼32 Tf molecules on the surface. DLC was 4.4%. CCK-8 assay demonstrated much stronger cytotoxicity of Tf-NP-Dox to C6 glioma cells compared to NP-Dox or Dox. HPLC assay showed that Tf-NP-Dox transported Dox into C6 cells with high efficiency. In vivo, Tf-NP-Dox could transport Dox into tumors compare to contralateral part, with tumor inhibitory ratio and survival higher than NP-Dox or Dox. Taken together, our results suggest that Tf-NP-Dox exhibits better therapeutic effects against glioma both in vitro and in vivo, and is a potential nano-scale drug delivery system for glioma chemotherapy.


Asunto(s)
Antineoplásicos/administración & dosificación , Materiales Biocompatibles/química , Neoplasias Encefálicas/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Portadores de Fármacos , Glioma/tratamiento farmacológico , Nanopartículas/química , Transferrina/química , Animales , Neoplasias Encefálicas/patología , Cromatografía Líquida de Alta Presión , Endocitosis , Glioma/patología , Humanos , Microscopía Electrónica de Transmisión , Trasplante de Neoplasias , Ratas , Solventes/química
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