RESUMEN
The mixed linear model has been widely used in genome-wide association studies (GWAS), but its application to multi-locus GWAS analysis has not been explored and assessed. Here, we implemented a fast multi-locus random-SNP-effect EMMA (FASTmrEMMA) model for GWAS. The model is built on random single nucleotide polymorphism (SNP) effects and a new algorithm. This algorithm whitens the covariance matrix of the polygenic matrix K and environmental noise, and specifies the number of nonzero eigenvalues as one. The model first chooses all putative quantitative trait nucleotides (QTNs) with ≤ 0.005 P-values and then includes them in a multi-locus model for true QTN detection. Owing to the multi-locus feature, the Bonferroni correction is replaced by a less stringent selection criterion. Results from analyses of both simulated and real data showed that FASTmrEMMA is more powerful in QTN detection and model fit, has less bias in QTN effect estimation and requires a less running time than existing single- and multi-locus methods, such as empirical Bayes, settlement of mixed linear model under progressively exclusive relationship (SUPER), efficient mixed model association (EMMA), compressed MLM (CMLM) and enriched CMLM (ECMLM). FASTmrEMMA provides an alternative for multi-locus GWAS.
Asunto(s)
Algoritmos , Proteínas de Arabidopsis/genética , Arabidopsis/genética , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple , Teorema de Bayes , Simulación por Computador , Modelos Lineales , Modelos Genéticos , Herencia Multifactorial , FenotipoRESUMEN
By integrating the characteristics of each therapy modality and material chemistry, a multitherapy modality is put forward: tumor starvation triggered synergism with sensitized chemotherapy. Following starvation-induced amplification of pathological abnormalities in tumors, chemotherapy is arranged to be locally activated and accurately reinforced to perfect multitherapy synergism from spatial and temporal perspectives. To this end, glucose oxidase (GOD) and a hypoxic prodrug of tirapazamine (TPZ) are loaded in acidity-decomposable calcium carbonate (CaCO3 ) nanoparticles concurrently tethered by hyaluronic acid. This hybrid nanotherapeutic shows a strong tendency to accumulate in tumors postinjection due to the cooperation between passive and active targeting mechanisms. The GOD-driven oxidation reaction deprives tumors of glucose for starvation therapy and concomitantly induces tumorous abnormality amplifications including elevated acidity and exacerbated hypoxia. Programmatically, the acidity amplification causes CaCO3 decomposition, offering not only spatial control over the liberation of embedded TPZ just within tumors but also the temporal control over timely chemotherapy initiation to match the occurrence of hypoxia amplification and thus benefiting perfect synergism between starvation therapy and chemotherapy.
Asunto(s)
Antineoplásicos/química , Carbonato de Calcio/química , Nanopartículas/química , Profármacos/química , Tirapazamina/química , Glucosa Oxidasa/metabolismo , Ácido Hialurónico/químicaRESUMEN
Multidrug resistance (MDR) remains one of the biggest obstacles in chemotherapy of tumor mainly due to P-glycoprotein (P-gp)-mediated drug efflux. Here, a transformable chimeric peptide is designed to target and self-assemble on cell membrane for encapsulating cells and overcoming tumor MDR. This chimeric peptide (C16 -K(TPE)-GGGH-GFLGK-PEG8 , denoted as CTGP) with cathepsin B-responsive and cell membrane-targeting abilities can self-assemble into nanomicelles and further encapsulate the therapeutic agent doxorubicin (termed as CTGP@DOX). After the cleavage of the Gly-Phe-Leu-Gly (GFLG) sequence by pericellular overexpressed cathepsin B, CTGP@DOX is dissociated and transformed from spherical nanoparticles to nanofibers due to the hydrophilic-hydrophobic conversion and hydrogen bonding interactions. Thus obtained nanofibers with cell membrane-targeting 16-carbon alkyl chains can adhere firmly to the cell membrane for cell encapsulation and restricting DOX efflux. In comparison to free DOX, 45-time higher drug retention and 49-fold greater anti-MDR ability of CTGP@DOX to drug-resistant MCF-7R cells are achieved. This novel strategy to encapsulate cells and reverse tumor MDR via morphology transformation would open a new avenue towards chemotherapy of tumor.
Asunto(s)
Portadores de Fármacos/química , Nanopartículas/química , Péptidos/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Membrana Celular/metabolismo , Doxorrubicina/química , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Células MCF-7RESUMEN
In this work, a ZnO based nanococktail with programmed functions is designed and synthesized for self-synergistic tumor targeting therapy. The nanococktail can actively target tumors via specific interaction of hyaluronic acid (HA) with CD44 receptors and respond to HAase-rich tumor microenvironment to induce intracellular cascade reaction for controlled therapy. The exposed cell-penetrating peptide (R8) potentiates the cellular uptake of therapeutic nanoparticles into targeted tumor cells. Then ZnO cocktail will readily degrade in acidic endo/lysosomes and induce the production of desired reactive oxygen species (ROS) in situ. The destructive ROS not only leads to serious cell damage but also triggers the on-demand drug release for precise chemotherapy, thus achieving enhanced antitumor efficiency synergistically. After tail vein injection of ZnO cocktail, a favorable tumor apoptosis rate (71.2 ± 8.2%) is detected, which is significantly superior to that of free drug, doxorubicin (12.9 ± 5.2%). Both in vitro and in vivo studies demonstrate that the tailor-made ZnO cocktail with favorable biocompatibility, promising tumor specificity, and self-synergistically therapeutic capacity opens new avenues for cancer therapy.
Asunto(s)
Espacio Intracelular/metabolismo , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Citometría de Flujo , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
OBJECTIVE: To explore clinical effect of vancomycin calcium sulfate combined with internal fixation on calcaneal beak-like fracture secondary to calcaneal osteomyelitis caused by diabetic foot. METHODS: From April 2018 to October 2021, a retrospective analysis was performed on 5 patients with calcaneal bone osteomyelitis secondary to diabetic foot, including 2 males and 3 females, aged from 48 to 60 years old;diabetes course ranged from 5 to 13 years;the courses of diabetic foot disease ranged from 18 to 52 days;5 patients were grade â ¢ according to Wagner classification. All patients were treated with debridement, vancomycin bone cement implantation, negative pressure aspiration at stageâ , vancomycin calcium sulfate and internal fixation at stageâ ¡for calcaneal beak-like fracture. Surgical incision and fracture healing time were recorded, and the recurrence of osteomyelitis was observed. American Orthopedic Foot Andankle Society (AOFAS) score and exudation at 12 months after operation were evaluated. RESULTS: Five patients were successfully completed operation without lower extremity vascular occlusion, and were followed up for 16 to 36 months. The wound healing time after internal fixation ranged from 16 to 26 days, and healing time of fractures ranged from 16 to 27 weeks. AOFAS score ranged from 65 to 91 at 12 months after operation, and 2 patients got excellent result, 2 good and 1 fair. Among them, 1 patient with skin ulcer on the back of foot caused by scalding at 5 months after operation (non-complication), was recovered after treatment;the wound leakage complication occurred in 2 patients, and were recovered after dressing change. No osteomyelitis or fracture occurred in all patients. CONCLUSION: Vancomycin calcium sulfate with internal fixation in treating calcaneal osteomyelitis secondary to calcaneal osteomyelitis caused by diabetic foot could not only control infection, but also promote fracture healing, and obtain good clinical results.
Asunto(s)
Calcáneo , Pie Diabético , Fijación Interna de Fracturas , Osteomielitis , Humanos , Masculino , Persona de Mediana Edad , Femenino , Osteomielitis/cirugía , Osteomielitis/tratamiento farmacológico , Osteomielitis/etiología , Pie Diabético/cirugía , Calcáneo/lesiones , Calcáneo/cirugía , Estudios Retrospectivos , Fijación Interna de Fracturas/métodos , Fracturas Óseas/complicaciones , Fracturas Óseas/cirugíaRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of Solitaire(TM) AB neurovascular stenting-assisted coil embolization for patients with wide-necked or dissecting aneurysms. METHODS: The clinical results and prognosis from a consecutive series of 38 patients with 40 wide-necked or dissecting aneurysms aneurysms who treated by Solitaire(TM) AB neurovascular stenting-assisted coil embolization from August 2010 to January 2012 was retrospectively analyzed. There were 12 male and 26 female patients, the age was 21 - 78 years (mean 55 years). Thirty-one cases were confirmed wide-neck aneurysms and 9 cases were dissection aneurysms by DSA. Acute subarachnoed hemorrhage due to the rupture of aneurysms was seen in 28 cases (according Hunt-Hess scale, 1 case of Class I, 20 cases of Class II, 4 cases of Class III, 3 cases of Class IV), 1 case was traumatic intracranial aneurysm, 1 case was misdiagnosed during the operation of pituitary adenoma by the approach of transsphenoid, and unruptured aneurysms were seen in 8 cases. The aneurysms were located at the posterior communicating segment of internal carotid artery (21 cases), the supraclinoid segment of internal carotid artery (6 cases), the cavernous segment of internal carotid artery (3 cases), the anterior communicating artery (1 case), and the vertebral artery (9 cases). The patients were performed DSA and Glasgow outcome score (GOS) to evaluate the prognosis 6 months after surgery. RESULTS: Forty stents were used and all remodeling device were achieved successful position. Owing to acute thrombosis in 3 patients, the stents were retrieved successfully. The proportion of patients in whom Raymond class 1 occlusion was obtained in 31 cases (77.5%), Raymond class 2 occlusion in 5 cases (12.5%) and Raymond class 3 occlusion in 4 cases (10.0%). The follow-up was 3 to 12 months (median 6 months). The results of DSA indicated none of the patients' anuerysm was recurred; and GOS was applied to evaluate the prognosis of patients after 3 months. Of 38 patients, 34 recovered well, 3 moderately disabled, 1 patient died. CONCLUSIONS: It is safe to embolize aneurysms with Solitaire(TM) AB neurovascular stenting-assisted coil; meanwhile, the stents can be retrieved when acute thrombosis to reduce the complications.
Asunto(s)
Disección Aórtica/terapia , Embolización Terapéutica/instrumentación , Aneurisma Intracraneal/terapia , Stents , Adulto , Anciano , Angiografía Cerebral , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVE: To investigate the anti-oxidant and anti-inflammatory effects of ethanol extract of Polygala sibirica L. var megalopha Fr. (EEP) on RAW264.7 mouse macrophages. METHODS: RAW264.7 cells were pretreated with 0-200 µg/mL EEP or vehicle for 2 h prior to exposure to 1 µg/mL lipopolysaccharide (LPS) for 24 h. Nitric oxide (NO) and prostaglandin (PGE2) production were determined by Griess reagent and enzyme-linked immunosorbent assay (ELISA), respectively. The mRNA levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin-1beta (IL-1ß), and IL-6 were determined using reverse transcription polymerase chain reaction (RT-PCR). Western blot assay was used to determine the protein expressions of iNOS, COX-2, phosphorylation of extracellular regulated protein kinases (ERK1/2), c-Jun N-terminal kinase (JNK), inhibitory subunit of nuclear factor Kappa B alpha (Iκ B-α) and p38. Immunofluorescence was used to observe the nuclear expression of nuclear factor-κ B p65 (NF-κ B p65). Additionally, the anti-oxidant potential of EEP was evaluated by reactive oxygen species (ROS) production and the activities of catalase (CAT) and superoxide dismutase (SOD). The 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl (OH), superoxide anion (O2-) radical and nitrite scavenging activity were also measured. RESULTS: The total polyphenol and flavonoid contents of EEP were 23.50±2.16 mg gallic acid equivalent/100 g and 43.78±3.81 mg rutin equivalent/100 g. With EEP treatment (100 and 150 µg/mL), there was a notable decrease in NO and PGE2 production induced by LPS in RAW264.7 cells by downregulation of iNOS and COX-2 mRNA and protein expressions (P<0.01 or P<0.05). Furthermore, with EEP treatment (150 µg/mL), there was a decrease in the mRNA expression levels of TNF-α, IL-1ß and IL-6, as well as in the phosphorylation of ERK, JNK and p38 mitogen-activated protein kinase (MAPK, P<0.01 or P<0.05), by blocking the nuclear translocation of NF-κ B p65 in LPS-stimulated cells. In addition, EEP (100 and 150 µg/mL) led to an increase in the anti-oxidant enzymes activity of SOD and CAT, with a concomitant decrease in ROS production (P<0.01 or P<0.05). EEP also indicated the DPPH, OH, O2- radical and nitrite scavenging activity. CONCLUSION: EEP inhibited inflammatory responses in activated macrophages through blocking MAPK/NF-κ B pathway and protected against oxidative stress.
Asunto(s)
Antioxidantes , Polygala , Animales , Ratones , Antioxidantes/farmacología , Lipopolisacáridos/farmacología , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Etanol/química , Interleucina-6/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/química , Especies Reactivas de Oxígeno/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Nitritos/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Superóxido Dismutasa/metabolismo , ARN Mensajero , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismoRESUMEN
The frequency of drought will increase under further warming. The increase in atmospheric CO2 concentration, along with more frequent drought, will affect crop growth. We examined the changes of cell structure, photosynthetic physiology, antioxidant enzymes, osmotic regulatory substances, and yield of foxtail millet (Setaria ita-lica) leaves under different CO2 concentrations (ambient air CO2 concentration and ambient atmospheric CO2 concentration + 200 µmol·mol-1) and water treatment (soil moisture content maintained at 45%-55%, and 70%-80% of field capacity, representing mild drought and normal water condition, respectively). The results showed that elevated CO2 concentration increased the number of starch grains, the area of single starch grains, and the total area of starch grains in the chloroplast of millet mesophyll cells. Under mild drought condition, elevated CO2 concentration increased net photosynthetic rate of millet leaves at the booting stage by 37.9%, but did not affect water use efficiency at this stage. Elevated CO2 concentration increased net photosynthetic rate and water use efficiency of millet leaves under mild drought condition at the filling stage by 15.0% and 44.2%, respectively. Under mild drought condition, elevated CO2 concentration increased the content of peroxidase (POD) and soluble sugar in millet leaves at the booting stage by 39.3% and 8.0%, respectively, but decreased proline content by 31.5%. It increased the content of POD in millet leaves at the filling stage by 26.5% but decreased the content of MDA and proline by 37.2% and 39.3%, respectively. Under mild drought condition, elevated CO2 concentration significantly increased the number of grain spikes by 44.7% and yield by 52.3% in both years compared with normal water condition. The effect of elevated CO2 concentration on grain yield under mild drought conditions was higher than that under normal water condition. Under mild drought conditions, elevated CO2 concentration increased leaf thickness, vascular bundle sheath cross-sectional area, net photosynthetic rate, and water use efficiency of millet, improved the antioxidant oxidase activity, and changed the concentration of osmotic regulatory substances, alleviated the nega-tive effect of drought on foxtail millet, and finally increased the number of grains per ear and yield of foxtail millet. This study would provide a theoretical basis for millet production and sustainable agricultural development in arid areas under future climate change.
Asunto(s)
Setaria (Planta) , Setaria (Planta)/fisiología , Dióxido de Carbono , Antioxidantes , Sequías , Prolina , Almidón/farmacologíaRESUMEN
Photodynamic therapy (PDT) is a promising treatment modality for tumor suppression. However, the hypoxic state of most solid tumors might largely hinder the efficacy of PDT. Here, a functional covalent organic framework (COF) is fabricated to enhance PDT efficacy by remodeling the tumor extracellular matrix (ECM). Anti-fibrotic drug pirfenidone (PFD) is loaded in an imine-based COF (COFTTA-DHTA) and followed by the decoration of poly(lactic-co-glycolic-acid)-poly(ethylene glycol) (PLGA-PEG) to fabricate PFD@COFTTA-DHTA@PLGA-PEG, or PCPP. After injected intravenously, PCPP can accumulate and release PFD in tumor sites, leading to down-regulation of ECM compenents such as hyaluronic acid (HA) and collagen I. Such depletion of tumor ECM reduces the intratumoral solid stress, a compressive force exerted by the ECM and cells, decompresses tumor blood vessels, and increases the density of effective vascular areas, resulting in significantly improved oxygen supply in tumor. Furthermore, PCPP-mediated tumor ECM depletion also enhances the tumor uptake of subsequently injected Protoporphyrinl IX (PPIX)-conjugated peptide formed nanomicelles (NM-PPIX) due to the improved enhanced permeability and retention (EPR) effect. Both the alleviated tumor hypoxia and improved tumor homing of photosensitizer (PS) molecules after PCPP treatment significantly increase the reactive oxygen species (ROS) generation in tumor and therefore realize greatly enhanced PDT effect of tumor in vivo.
Asunto(s)
Estructuras Metalorgánicas , Nanopartículas , Neoplasias , Fotoquimioterapia , Línea Celular Tumoral , Matriz Extracelular , Humanos , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéuticoRESUMEN
Photothermal therapy (PTT) is an effective treatment modality with high selectivity for tumor suppression. However, the inflammatory responses caused by PTT may lead to adverse reactions including tumor recurrence and therapeutic resistance, which are regarded as major problems for PTT. Here, a near-infrared (NIR) light-responsive nanoreactor (P@DW/BC) is fabricated to simultaneously realize tumor PTT and carbon monoxide (CO)-mediated anti-inflammatory therapy. Defective tungsten oxide (WO3) nanosheets (DW NSs) are decorated with bicarbonate (BC) via ferric ion-mediated coordination and then modified with polyethylene glycol (PEG) on the surface to fabricate PEG@DW/BC or P@DW/BC nanosheets. Upon 808 nm NIR laser irradiation, the DW content in P@DW/BC can serve as not only a photothermal agent to realize photothermal conversion but also a photocatalyst to convert carbon dioxide (CO2) to CO. In particular, the generated heat can also trigger the decomposition of BC to produce CO2 near the NSs, thus enhancing the photocatalytic CO generation. Benefiting from the efficient hyperthermia and CO generation under single NIR laser irradiation, P@DW/BC can realize effective thermal ablation of tumor and simultaneous inhibition of PTT-induced inflammation.
RESUMEN
Lactate, the main contributor to the acidic tumor microenvironment, not only promotes the proliferation of tumor cells, but also closely relates to tumor invasion and metastasis. Here, a tumor targeting nanoplatform, designated as Me&Flu@MSN@MnO2-FA, was fabricated for effective tumor suppression and anti-metastasis by interfering with lactate metabolism of tumor cells. Metformin (Me) and fluvastatin sodium (Flu) were incorporated into MnO2-coated mesoporous silicon nanoparticles (MSNs), the synergism between Me and Flu can modulate the pyruvate metabolic pathway to produce more lactate, and concurrently inhibit lactate efflux to induce intracellular acidosis to kill tumor cells. As a result of the restricted lactate efflux, the extracellular lactate concentration is reduced, and the ability of the tumor cells to migrate is also weakened. This ingenious strategy based on Me&Flu@MSN@MnO2-FA showed an obvious inhibitory effect on tumor growth and resistance to metastasis.
Asunto(s)
Fluvastatina , Lactatos/metabolismo , Compuestos de Manganeso , Metformina , Nanopartículas , Neoplasias , Microambiente Tumoral/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Fluvastatina/química , Fluvastatina/farmacocinética , Fluvastatina/farmacología , Ácido Fólico/metabolismo , Humanos , Compuestos de Manganeso/química , Compuestos de Manganeso/farmacocinética , Compuestos de Manganeso/farmacología , Metformina/química , Metformina/farmacocinética , Metformina/farmacología , Nanopartículas/química , Nanopartículas/uso terapéutico , Metástasis de la Neoplasia , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Porosidad , Silicio/química , Silicio/farmacocinética , Silicio/farmacologíaRESUMEN
Selectively attenuating the protection offered by heat shock protein 90 (HSP90), which is indispensable for the stabilization of the essential regulators of cell survival and works as a cell guardian under oxidative stress conditions, is a potential approach to improve the efficiency of cancer therapy. Here, we designed a biodegradable nanoplatform (APCN/BP-FA) based on a Zr(iv)-based porphyrinic porous coordination network (PCN) and black phosphorus (BP) sheets for efficient photodynamic therapy (PDT) by enhancing the accumulation of the nanoplatforms in the tumor area and attenuating the protection of cancer cells. Owing to the favorable degradability of BP, the nanosystem exhibited accelerated the release of the HSP90 inhibitor tanespimycin (17-AAG) and an apparent promotion in the reactive oxygen species (ROS) yield of PCN as well as expedited the degradation of the PCN-laden BP nanoplatforms. Both in vitro and in vivo results revealed that the elevated amounts of ROS and reduced cytoprotection in tumor cells were caused by the nanoplatforms. This strategy may provide a promising method for attenuating cytoprotection to aid efficient photodynamic therapy.
Asunto(s)
Estructuras Metalorgánicas/química , Neoplasias/tratamiento farmacológico , Fósforo/química , Fotoquimioterapia/métodos , Animales , Benzoquinonas/química , Benzoquinonas/uso terapéutico , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Ácido Fólico/química , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/uso terapéutico , Estructuras Metalorgánicas/farmacocinética , Estructuras Metalorgánicas/uso terapéutico , Ratones , Nanoestructuras/química , Nanoestructuras/uso terapéutico , Neoplasias/metabolismo , Fósforo/farmacocinética , Fósforo/uso terapéutico , Porosidad , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Circonio/química , Circonio/farmacocinética , Circonio/uso terapéuticoRESUMEN
To enhance the treatment efficiency in tumor therapy, we developed a tumor-targeting protein-based delivery system, DOX&ICG@BSA-KALA/Apt, to efficiently integrate multimodal therapy with tumor imaging and realize synchronous photodynamic therapy/photothermal therapy/chemotherapy. In the delivery system, a chemotherapeutic drug (doxorubicin, DOX) and an optotheranostic agent (indocyanine green, ICG) were co-loaded in bovine serum albumin (BSA) via a hydrophobic-interaction-induced self-assembly to form stable DOX&ICG@BSA nanoparticles. After the decoration of a surface layer composed of a tumor-targeting aptamer (AS1411) and a cell-penetrating peptide (KALA), the obtained DOX&ICG@BSA-KALA/Apt nanoparticles exhibit a significantly improved multimodal cancer therapeutic efficiency due to the enhanced cancer cellular uptake mediated by AS1411 and KALA. In vitro and in vivo studies show that the multimodal theranostic system can efficiently inhibit tumor growth. In addition, the near-infrared fluorescent/photothermal dual-mode imaging enables accurate visualization of the therapeutic action in tumor sites. This study provides a facile strategy to construct self-assembled multimodal theranostic systems, and the functional protein-based theranostic system prepared holds great promise in multimodal cancer therapeutics.
Asunto(s)
Doxorrubicina/química , Portadores de Fármacos/química , Verde de Indocianina/química , Nanopartículas/química , Albúmina Sérica Bovina/química , Animales , Aptámeros de Nucleótidos/química , Supervivencia Celular/efectos de los fármacos , Péptidos de Penetración Celular/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Portadores de Fármacos/metabolismo , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Oligodesoxirribonucleótidos/química , Oxígeno Singlete/química , Propiedades de Superficie , Nanomedicina Teranóstica , Distribución TisularRESUMEN
An innovative tungsten-based multifunctional nanoplatform composed of polyethylene glycol (PEG)-modified tungsten nitride nanoparticles (WN NPs) is constructed for tumor treatment. The PEG-WN NPs not only possess strong near-infrared (NIR) absorbance, high photothermal conversion efficiency, and excellent photothermal stability, but also effectively inhibit tumor cells upon 808 nm laser irradiation. After coating with thiolated (2-hydroxypropyl)-ß-cyclodextrin (MUA-CD) on the surface, such a nanoplatform can also be used for drug delivery (such as DOX) and presents a synergistic tumor inhibition effect both in vitro and in vivo. Furthermore, the PEG-WN NPs present good contrasting capability for X-ray computed tomography (CT) and photoacoustic (PA) imaging. With PA/CT imaging, the tumor can be accurately positioned for precise treatment. It is worth mentioning that PEG-WN NPs are biodegradable and could be effectively excreted from the body with no appreciable toxicity in vivo. It is expected that this biocompatible multifunctional nanoplatform can serve as a potential candidate for tumor treatment in future clinical applications.
Asunto(s)
Nanopartículas del Metal/química , Tungsteno/química , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Portadores de Fármacos/química , Femenino , Hipertermia Inducida , Rayos Láser , Nanopartículas del Metal/toxicidad , Ratones , Ratones Endogámicos BALB C , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Tamaño de la Partícula , Técnicas Fotoacústicas , Fototerapia , Polietilenglicoles/química , Nanomedicina Teranóstica , Tomografía Computarizada por Rayos X , beta-Ciclodextrinas/químicaRESUMEN
Carbon monoxide (CO) is regarded as a potential therapeutic agent with multiple beneficial functions for biomedical applications. In this study, a versatile CO nanogenerator (designated as PPOSD) was fabricated and developed for tumor therapy and anti-inflammation. Partially oxidized tin disulfide (SnS2) nanosheets (POS NSs) were decorated with a tumor-targeting polymer (polyethylene glycol-cyclo(Asp-d-Phe-Lys-Arg-Gly), PEG-cRGD), followed by the loading of chemotherapeutic drug doxorubicin (DOX) to prepare polymer@POS@DOX, or PPOSD. After injected intravenously, PPOSD could selectively accumulate in tumor tissue via the cRGD-mediated tumor recognition. Upon 561 nm laser irradiation, the POS moiety in PPOSD can photoreduce CO2 to CO, which significantly sensitized the chemotherapeutic effect of DOX. The POS in PPOSD can also act as a photothermal agent for effective photothermal therapy (PTT) of the tumor upon 808 nm laser irradiation. Furthermore, the generated CO can simultaneously decrease the inflammatory reaction caused by PTT. Blood analysis and hematoxylin-eosin staining of major organs showed that no obvious systemic toxicity was induced after the treatment, suggesting good biosafety of PPOSD. This versatile CO nanogenerator will find great potential for both enhanced tumor inhibition and anti-inflammation.
Asunto(s)
Monóxido de Carbono/farmacología , Inflamación/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Dióxido de Carbono/química , Monóxido de Carbono/química , Línea Celular Tumoral , Disulfuros/química , Disulfuros/farmacología , Doxorrubicina/farmacología , Humanos , Inflamación/patología , Ratones , Nanopartículas/química , Neoplasias/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Understanding the genetic function of the forage quality-related traits, including crude protein (CP), neutral detergent fiber (NDF), acid detergent fiber (ADF), hemicellulose (HC), and cellulose (CL) contents, is essential for the identification of forage quality genes and selection of effective molecular markers in sorghum. In this study, we genotyped 245 sorghum accessions by 85,585 single-nucleotide polymorphisms (SNPs) and obtained the phenotypic data from four environments. The SNPs and phenotypic data were applied to multi-locus genome-wide association studies (GWAS) with the mrMLM software. A total of 42 SNPs were identified to be associated with the five forage quality-related traits. Moreover, three and two quantitative trait nucleotides (QTNs) were simultaneously detected among them by three and two multi-locus methods, respectively. One QTN on chromosome 5 was found to be associated simultaneously with CP, NDF, and ADF. Furthermore, 3, 2, 2, 5, and 2 candidate genes were identified to be responsible for CP, NDF, ADF, HC, and CL contents, respectively. These results provided insightful information of the forage quality-related traits and would facilitate the genetic improvement of sorghum forage quality in the future.
RESUMEN
Non-apoptotic ferroptosis is of clinical importance because it offers a solution to the inevitable biocarriers of traditional apoptotic therapeutic means. Inspired by industrial electro-Fenton technology featured with electrochemical iron cycling, we construct ferrous-supply-regeneration nanoengineering to intervene tumorous iron metabolism for enhanced ferroptosis. Fe3+ ion and naturally derived tannic acid (TA) spontaneously form a network-like corona onto sorafenib (SRF) nanocores. The formed SRF@FeIIITA nanoparticles can respond to a lysosomal acid environment with corona dissociation, permitting SRF release to inhibit GPX4 enzyme for ferroptosis initiation. TA is arranged to chemically reduce the liberated and the ferroptosis-generated Fe3+ to Fe2+, offering iron redox cycling to, thus, effectively produce lipid peroxide required in ferroptosis. Sustained Fe2+ supply leads to long-term cytotoxicity, which is identified to be specific to H2O2-overloaded cancer cells but minimal in normal cells. SRF@FeIIITA-mediated cell death proves to follow the ferroptosis pathway and strongly inhibits tumor proliferation. Moreover, SRF@FeIIITA provides a powerful platform capable of versatile integration between apoptosis and non-apoptosis means. Typically, photosensitizer-adsorbed SRF@FeIIITA demonstrates rapid tumor imaging owing to the acid-responsive fluorescence recovery. Together with ferroptosis, imaging-guided photodynamic therapy induces complete tumor elimination. This study offers ideas about how to advance anticancer ferroptosis through rational material design.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Nanotecnología , Neoplasias/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Células 3T3 , Animales , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Endogámicos BALB C , Neoplasias/diagnóstico por imagen , Fármacos Fotosensibilizantes/químicaRESUMEN
OBJECTIVE: To discuss the avail of balloon and stent-assisted Guglielmi detachable coil (GDC) placement in treatment of wide-necked cerebral aneurysm. METHODS: Eighty-seven patients with 92 wide-necked aneurysms undergone endovascular procedures using the balloon and stent-assisted remodeling technique. Respectively, appropriate Neuroform stents delivered with a 5 mm landing zone on either side of the aneurysm neck, the microcatheter entered through the interstice, aneurysms were embolized at one or several times. Two catheters were used in balloon-remodeling technique, balloon were inflated across the neck of the aneurysms after the microcatheter entering the aneurysms, then the GDC were used to embolize the aneurysms. RESULTS: Thirty-one aneurysms were completely occluded, 3 subtotally (> 90%) and 1 incompletely (70% - 90%) occluded using stent-assisted technique, all carry arteries were unblocked, 3 patients with mild neurological dysfunction and no mortality. Fifty aneurysms were completely occluded and 4 incompletely occluded using balloon-assisted technique, 1 patients with mild neurological dysfunction and no mortality. Two aneurysms were completely occluded and 1 incompletely occluded using stent-assisted and balloon-assisted technique. The mean period of follow-up was 5.8 months. Rates of recanalization were 16.7% for stent-remodeling group and 12.5% for balloon-remodeling group. CONCLUSIONS: The stent and balloon-assisted remodeling technique are safe and effective in treating wide-necked aneurysms. Balloon-remodeling technique has more security comparing with stents.