RESUMEN
Pulmonary fibrosis (PF) is an age-related interstitial lung disease that results in notable morbidity and mortality. The Food and Drug Administration-approved drugs can decelerate the progression of PF; however, curing aged patients with severe fibrosis is ineffective because of insufficient accumulation of these drugs and wide necrocytosis of type II alveolar epithelial cells (AEC IIs). Here, we constructed a mesenchymal stem cell (MSC)-based nanoengineered platform via the bioconjugation of MSCs and type I collagenase-modified liposomes loaded with nintedanib (MSCs-Lip@NCAF) for treating severe fibrosis. Specifically, MSCs-Lip@NCAF migrated to fibrotic lungs because of the homing characteristic of MSCs and then Lip@NCAF was sensitively released. Subsequently, Lip@NCAF ablated collagen fibers, delivered nintedanib into fibroblasts, and inhibited fibroblast overactivation. MSCs differentiated into AEC IIs to repair alveolar structure and ultimately promote the regeneration of damaged lungs in aged mice. Our findings indicated that MSCs-Lip@NCAF could be used as a promising therapeutic candidate for PF therapy, especially in aged patients.
Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Fibrosis Pulmonar , Estados Unidos , Animales , Ratones , Fibrosis Pulmonar/terapia , Fibrosis Pulmonar/metabolismo , Pulmón/metabolismo , Células Epiteliales Alveolares , Células Madre Mesenquimatosas/metabolismoRESUMEN
A fundamental understanding of the reactivity evolution of nanosized clusters at an atomically precise level is pivotal to assemble desired materials with promising candidates. Benefiting from the tandem mass spectrometer coupled with a high-temperature ion-trap reactor, the reactions of mass-selected Con- (n = 5-25) clusters with CO2 were investigated and the increased reactivity of Co20-25- was newly discovered herein. This finding marks an important step to understand property evolution of subnanometer metal clusters (Co25-, â¼0.8 nm) atom-by-atom. The reasons behind the increased reactivity of Co20-25- were proposed by analyzing the reactions of smaller Co6-8- clusters that exhibit significantly different reactivity toward CO2, in which a lower electron affinity of Con contributes to the capture of CO2 while the flexibility of Con- could play vital roles to stabilize reaction intermediates and suppress the barriers of O-CO rupture and CO desorption.
RESUMEN
The key to optimizing energy-consuming catalytic conversions lies in acquiring a fundamental understanding of the nature of the active sites and the mechanisms of elementary steps at an atomically precise level, while it is challenging to capture the crucial step that determines the overall temperature of a real-life catalytic reaction. Herein, benefiting from a newly-developed high-temperature ion trap reactor, the reverse water-gas shift (CO2 + H2 â CO + H2O) reaction catalyzed by the Rhn- (n = 3-11) clusters was investigated under variable temperatures (298-783 K) and the critical temperature that each elementary step (Rhn- + CO2 and RhnO- + H2) requires to take place was identified. The Rh4- cluster strikingly surpasses other Rhn- clusters to drive the catalysis at a mild starting temperature (â¼440 K). This finding represents the first example that a specifically sized cluster catalyst that works under an optimum condition can be accurately filtered by using state-of-the-art mass spectrometric experiments and rationalized by quantum-chemical calculations.
RESUMEN
Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial lung disease in which collagen progressively deposits in the supporting framework of the lungs. The pathological collagen creates a recalcitrant barrier in mesenchyme for drug penetration, thus greatly restricting the therapeutical efficacy. On the other hand, this overloaded collagen is gradually exposed to the bloodstream at fibrotic sites because of the vascular hyperpermeability, thus serving as a potential target. Herein, pathological collagen targeting and penetrating liposomes (DP-CC) were constructed to deliver anti-fibrotic dual drugs including pirfenidone (PFD) and dexamethasone (DEX) deep into injured alveoli. The liposomes were co-decorated with collagen binding peptide (CBP) and collagenase (COL). CBP could help vehicle recognize the pathological collagen and target the fibrotic lungs efficiently because of its high affinity to collagen, and COL assisted in breaking through the collagen barrier and delivering vehicle to the center of injured sites. Then, the released dual drugs developed a synergistic anti-fibrotic effect to repair the damaged epithelium and remodel the extracellular matrix (ECM), thus rebuilding the lung architecture. This study provides a promising strategy to deliver drugs deep into pathological collagen accumulated sites for the enhanced treatment of IPF.
Asunto(s)
Fibrosis Pulmonar Idiopática , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Liposomas/metabolismo , Colágeno/metabolismo , Pulmón/metabolismo , Matriz Extracelular/metabolismo , Fibrosis , Fibroblastos/metabolismoRESUMEN
Noble metals dispersed on transition-metal carbides exhibit extraordinary activity in CO2 catalytic conversion and bimetallic carbides generated at the interface were proposed to contribute to the observed activity. Heteronuclear metal carbide clusters (HMCCs) that compositionally resemble the bimetallic carbides are suitable models to get a fundamental understanding of the reactivity of the related condensed-phase catalysts, while the reaction of HMCCs with CO2 has not been touched in the gas phase. Herein, benefiting from the newly designed double ion trap reactors, the reaction of laser-ablation generated and mass-selected RhTaC2- clusters with CO2 was studied. The experimental results identified that RhTaC2- can reduce four CO2 molecules consecutively and generate the product RhTaC2O4-. The pivotal roles of Rh-Ta synergy and the C2 ligand in driving CO2 reduction were rationalized by theoretical calculations. The presence of an attached CO unit on the product RhTaC2O4- was evidenced by the collision-induced dissociation experiment, providing a fundamental strategy to alleviate carbon deposition under a CO2 atmosphere at elevated temperatures.
RESUMEN
OBJECTIVE: We want to investigate the effect of aquaporin-4 (AQP4) on cerebral edema induced by ischemic stroke in rats and explore whether inhibiting the expression of AQP4 through acetazolamide (AZA) could attenuate brain edema and protect cerebral function. METHODS: The Sprague Dawley (SD) rats were randomly divided into four groups: sham + saline group, sham + AZA group, AZA intervention group, and nonintervention group. Each group was divided into five subgroups according to the time of cerebral ischemia (6 h, 1 day, 3 days, 5 days, and 7 days). The model of cerebral infarction in rats was adopted by means of the bilateral carotid arteries ligation (2-VO) method. The rats in intervention group were given intraperitoneal injection of AZA (35 mg/kg/day). Hematoxylin-eosin staining was performed for pathological analysis of the infarcted area. The brain water content was calculated to evaluate the degree of brain edema. The messenger RNA (mRNA) and protein expressions of AQP4 in the brain were measured by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. RESULTS: Significant cerebral pathological damages were found in ischemic stroke rats. The brain water content, protein, and mRNA expression of AQP4 of the intervention and nonintervention groups were markedly higher than those of the sham groups. By contrast, AZA administration reduced the brain water content, whereas improved cerebral dysfunction was induced by ischemic stroke. Moreover, AZA obviously reduced the protein and mRNA expression of AQP4 after ischemic stroke in rats' brains. CONCLUSIONS: The expression of AQP4 was closely related to cerebral edema induced by ischemic stroke. Decreasing the expression of AQP4 mRNA by AZA administration can effectively relieve cerebral edema and decrease cerebral pathological damage.
Asunto(s)
Edema Encefálico , Accidente Cerebrovascular Isquémico , Acetazolamida/farmacología , Animales , Acuaporina 4/metabolismo , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/etiología , Edema Encefálico/metabolismo , ARN Mensajero , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Clear cell sarcoma of the kidney (CCSK) is a rare and aggressive tumor. This study aims to describe the clinical characteristics and outcomes of CCSK patients in one of the largest pediatric medical centers in China. METHODS: We included all patients diagnosed with CCSK between January 2008 and March 2019 at the Children's Hospital of Chongqing Medical University, China. The patients' demographics, clinical presentation, and management were reviewed. Follow-up was continued until December 2019. RESULTS: In total, 41 CCSK patients (66% male) with a median age of 24 months (range 3-108 months) were identified. The stage distributions of stages I, II, III and IV were 42%, 34%, 24% and 0%, respectively. Preoperative chemotherapy was administered to 7/41 patients. All patients underwent radical nephrectomy and postoperative chemotherapy. The median number of lymph nodes sampled was 4 (range 1-12). Radiotherapy was applied in 8/41 patients. The 5-year event-free survival (EFS) and overall survival (OS) were 63.9% and 78.8%, respectively. Of the 41 patients, 11 patients experienced relapse at a median time of 19 months (range 5-72 months). The most common site of recurrence was the tumor bed (9/11). Young age was a significant adverse prognostic factor for EFS. CONCLUSIONS: The overall outcome of CCSK patients in our hospital is poorer than that in developed regions. More research is needed to clarify the underlying causes of poorer outcomes in young patients and improve outcomes. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: LEVEL IV.
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Neoplasias Renales , Sarcoma de Células Claras , Tumor de Wilms , Protocolos de Quimioterapia Combinada Antineoplásica , Niño , Preescolar , China , Femenino , Humanos , Lactante , Riñón/patología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/cirugía , Masculino , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Estudios Retrospectivos , Sarcoma de Células Claras/terapiaRESUMEN
Tbx6 is critical for somite specification and myogenesis initiation. It has been shown that Activin/Nodal, VegT/Nodal, FGF, and BMP signaling pathways are involved early in specifying mesoderm or later in patterning mesoderm, and Xnot plays roles in setting up the boundary between notochord and paraxial mesoderm. In this study, we introduce the dominant negative form of above genes into embryos to evaluate if they are responsible for regulating Tbx6 expression. The results show that: (1) Activin/Nodal and VegT/Nodal signals are necessary for both initiation and maintenance of Tbx6 expression, and Nodal is sufficient to induce ectopic Tbx6 expression; (2) FGF signal is necessary for the initiation and maintenance of Tbx6, but it is not sufficient to induce Tbx6 expression; (3) BMP is also necessary for the expression of Tbx6, and the induction of Tbx6 expression by BMP is dose dependent; (4) Xnot has no effect on the expression of Tbx6. Our results suggest that several signaling pathways are involved in regulating Tbx6 expression, and pave the route to reveal the molecular mechanism of initiating myogenesis.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Transducción de Señal , Factores de Transcripción/fisiología , Proteínas de Xenopus/fisiología , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Relación Dosis-Respuesta a Droga , Factores de Crecimiento de Fibroblastos/metabolismo , Genes Dominantes , Hibridación in Situ , Mesodermo/metabolismo , Proteína Nodal , Fenotipo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas de Dominio T Box , Factores de Transcripción/química , Factor de Crecimiento Transformador beta/metabolismo , Proteínas de Xenopus/química , Xenopus laevisRESUMEN
BACKGROUND: The timed-sequential chemotherapy regimen consisting of etoposide, mitoxantrone and cytarabine (EMA) is an effective therapy for relapsed or refractory acute myelogenous leukemia (AML). We postulated that granulocyte colony-stimulating factor (G-CSF) might enhance the cytotoxicity of EMA by increasing the proportion of leukemic blasts in S-phase. We added G-CSF to EMA (EMA-G) for therapy of advanced high-risk AML patients. METHODS: High-risk AML was defined as refractory, relapsed or secondary to either an antecedent hematologic disorder or exposure to cytotoxic agents. The patients were treated with one course of EMA-G consisting of mitoxantrone and cytarabine on days 1-3, and etoposide and cytarabine on days 8-10. G-CSF was started on day 4 and continued until absolute neutrophil count recovered. RESULTS: Thirty patients were enrolled. The median age was 51 years (range, 25-75). Seventeen (61%) patients had unfavorable cytogenetic karyotypes. Twenty (69%) patients had secondary AML. Ten (34%) had relapsed disease. Four (14%) had refractory AML. Three (10%) patients died from febrile neutropenia and sepsis. Major non-hematologic toxicity included hyperbilirubimenia, renal insufficiency, mucositis, diarrhea, nausea and vomiting, skin rash. A complete remission was achieved in 13 (46%) patients. Median overall survival was 9 months (range, 0.5-66). Median relapse-free survival (RFS) for those who had a CR was 3 months (range, 0.5-63) with RFS censored at the time of allogeneic bone marrow transplantation or peripheral stem cell transplantation for 6 of the patients. CONCLUSIONS: EMA-G is a safe and efficacious option for induction chemotherapy in advanced, high-risk AML patients. The activity of EMA may be increased if applied in patients with less advanced disease.