RESUMEN
In the current work, grifolin was obtained from the twigs and leaves of Daphne genkwa for the first time and displayed significant growth inhibition against human lung carcinoma A549 cells. Subsequent inâ vitro antitumor evaluation revealed that grifolin could induce remarkable cell apoptosis and G0/G1 phase arrest, as well as block cell migration and invasion. In addition, grifolin also disrupted cellular energy metabolism by inducing reactive oxygen species, reducing adenosine triphosphate and mitochondrial membrane potential, and damaging DNA synthesis. Further RNA-seq analysis demonstrated that treatment of grifolin on A549 cells led to gene enrichment in MAPK, PI3K/Akt and NF-κB signaling pathways, all of which were inhibited by grifolin according to immunoblotting experiments. Further mechanistical studies disclosed that the expression of a key upstream protein KRAS was also blocked, and the cell death triggered by grifolin could be rescued by a RAS activator ML-099. Moreover, pretreatment of ML-099 on A549 cells could reverse the grifolin-induced downregulation of key proteins in the three aforementioned pathways. These findings indicate that grifolin could induce cell death in A549 cell line by inhibiting KRAS-mediated multiple signaling pathways.
Asunto(s)
Proliferación Celular , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas p21(ras) , Transducción de Señal , Humanos , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Células A549 , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Movimiento Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , TerpenosRESUMEN
Low-power electronic devices play a pivotal role in the burgeoning artificial intelligence era. The study of such devices encompasses low-subthreshold swing (SS) transistors and neuromorphic devices. However, conventional field-effect transistors (FETs) face the inherent limitation of the "Boltzmann tyranny", which restricts SS to 60 mV decade-1 at room temperature. Additionally, FET-based neuromorphic devices lack sufficient conductance states for highly accurate neuromorphic computing due to a narrow memory window. In this study, we propose a pioneering PZT-enabled MoS2 floating gate transistor (PFGT) configuration, demonstrating a low SS of 46 mV decade-1 and a wide memory window of 7.2 V in the dual-sweeping gate voltage range from -7 to 7 V. The wide memory window provides 112 distinct conductance states for PFGT. Moreover, the PFGT-based artificial neural network achieves an outstanding facial-recognition accuracy of 97.3%. This study lays the groundwork for the development of low-SS transistors and highly energy efficient artificial synapses utilizing two-dimensional materials.
RESUMEN
Phytochemical investigation into the leaves and branches of Daphne genkwa afforded 25 meroterpenoids (1-16) including nine pairs of enantiomers (1a/1b-8a/8b and 12a/12b), among which 20 compounds have been reported in the present work for the first time. The structures with absolute configurations of the new molecules (excluding 10-13) were established via comprehensive spectroscopic analyses especially electronic circular dichroism (ECD) and Mosher's methods. A preliminary in vitro cell viability assay revealed remarkable cytotoxicities of selective compounds against A549 (lung), Hela (cervical), MDA-MB231 (breast) and MCF-7 (breast) cancer cells, and compound 8a showed the best inhibitory activity with IC50 values in the range of 3.12-4.67 µM toward the four cell lines. Subsequent in vitro antitumor evaluation of 8a disclosed that it could inhibit the proliferation and metastasis, as well as induce significant apoptosis and cycle arrest, of A549 cells. Further mechanistic investigations revealed that 8a could exert its antitumor activity via inhibiting the PI3K/Akt/mTOR signaling pathway.
Asunto(s)
Daphne , Humanos , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Células A549 , Serina-Treonina Quinasas TOR , Células HeLa , Transducción de SeñalRESUMEN
Chemical fractionation of the AcOEt partition, generated from the EtOH extract of the fruits of Schisandra chinensis, afforded a series of sesquiterpenyl constituents including two new cadinanes, a new eudesmane, two new widdranes (a handling artefact and a new natural product), a new bisabolane and two new natural cuparane enantiomers, along with 15 known structurally related analogs. Structures of the new compounds were unambiguously characterized by interpretation of detailed spectroscopic data including ESI-MS and 1D/2D NMR, with their absolute configurations being established by electronic circular dichroism (ECD) calculation and induced ECD experiment. The inhibitory effects of all the isolates against α-glucosidase and lipopolysaccharide (LPS) induced nitric oxide (NO) production in murine RAW264.7 macrophages, as well as their antibacterial and cytotoxic potential, were evaluated, with selective compounds showing moderate α-glucosidase and NO inhibitory activity. Notably, canangaterpene III exhibited the most significant NO inhibitory effect with an IC50 value of 31.50±1.49â µM.
RESUMEN
The objective of this study is to evaluate whether high-dose chemotherapy is more efficacious than standard-dose chemotherapy in the treatment of primary well-differentiated osteosarcoma. The Cochrane systematic evaluation method was adopted. A database search was conducted in MEDLINE, Embase, OVID, the Cochrane Central Register of Controlled Trials database and the Chinese Biomedical Literature CD-ROM Database. The quality of the included studies was jointly evaluated by two reviewers, and homogeneous studies were included for meta-analysis. A total of five studies were included in this meta-analysis, with 1,415 subjects with primary, nonmetastatic, well-differentiated osteosarcoma in the limbs. No statistically significant differences were found between the high-dose chemotherapy group and the low-dose group in 5-year event-free survival [RR 1.04, 95 %CI (0.95, 1.13)], 5-year overall survival [RR 1.02, 95 %CI (0.95, 1.10)], local recurrence rate [RR 0.90, 95 %CI (0.59, 1.39)], proportion of subjects with good histological response [RR 0.93, 95 %CI (0.81, 1.07)], or limb salvage rate [RR 0.97, 95 %CI (0.92, 1.02)]. A statistically significant difference was observed in the 5-year event-free survival between the subjects with good histological response to preoperative chemotherapy and the subjects with poor histological response [RR 1.55, 95 %CI (1.19, 2.00), P < 0.001]. High-dose chemotherapy did not show superior efficacy to low-dose chemotherapy in the treatment of primary well-differentiated osteosarcoma. Further high-quality randomized controlled trials are needed to provide additional reliable evidence for our observation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Óseas/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Neoplasias Óseas/patología , Diferenciación Celular , Humanos , Osteosarcoma/patología , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Four new flavanone-diarylheptanoid hetero dimers, typhatifolins A-D (1-4), were separated from the pollen of a widely distributed medicinal plant Typha angustifolia. Structures of these rare hybrids were elucidated by detailed interpretation of spectroscopic data, and their absolute configurations were determined on the basis of Mosher's method and ECD analyses. All the four compounds showed moderate to significant cytotoxicities against a panel of tumor cell lines with IC50 values ranging from 0.67 to 12.48 µM. Further in vitro antitumor evaluation for typhatifolin B (TTB, 2) on two breast cancer cells (4T1 and MDA-MB231) revealed that it could remarkably induce cell apoptosis and G0/G1 cycle arrest, as well as block cell migration and invasion. Mechanistically, TTB could exert its antitumor effect via activating the TGF-ß1 (transforming growth factor beta 1) signaling pathway as evidenced by RNA-seq analysis and immunoblotting experiments, which was further corroborated by treating cancer cells with a TGF-ß signaling inhibitor. Lastly, the in vivo anti breast cancer activity was demonstrated by applying the mixture of typhatifolins A-D to a preclinical animal model.
Asunto(s)
Neoplasias , Typhaceae , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Typhaceae/metabolismo , Proteínas Smad/metabolismo , Transducción de Señal , Línea Celular TumoralRESUMEN
Nine previously unreported lathyrane diterpenoids named euphorantesters A-I, along with 16 known analogues, have been separated from the tubers of Euphorbia antiquorum. Their structures were established by means of spectroscopic analyses, time-dependent density functional theory based electronic circular dichroism calculation and single crystal X-ray crystallography. Their reversal ability against P-glycoprotein-mediated multidrug resistance (MDR) in MCF-7/ADR cell line was then evaluated, and 15 ones exhibited moderate MDR reversal activity with reversal fold falling in the range of 1.12-13.15. The most active euphorantester B could effectively increase the sensitivity of MCF-7/ADR cell to adriamycin comparably to the reference drug verapamil.
RESUMEN
An intensive phytochemical investigation into the fruits of Schisandra chinensis afforded 28 triterpenoids incorporating diverse backbones with methyl-migration, ring-expansion and ring-opening features. Among them, ten compounds (1-10) including three likely extracting artefacts (8-10) were described for the first time. Their structures were fully characterized by comprehensive spectroscopic analyses, with the absolute configurations established via electronic circular dichroism and Mosher's NMR techniques. Preliminary biological evaluations revealed that nine isolates showed inhibitory activity against the hyperglycemic target α-glycosidase and 12 compounds exerted cytotoxicity toward three female tumor cell lines (Hela (cervical), MDA-MB231 and MCF-7 (breast)). Compound 6 exhibited the most promising potency on all the three tested cancer cells, and further assessment demonstrated that it could induce significant cell apoptosis and cycle arrest, as well as suppress cell migration, by regulating relevant proteins in MDA-MB231 cells.
Asunto(s)
Antineoplásicos Fitogénicos , Apoptosis , Frutas , Inhibidores de Glicósido Hidrolasas , Fitoquímicos , Schisandra , Triterpenos , Schisandra/química , Humanos , Frutas/química , Estructura Molecular , Triterpenos/farmacología , Triterpenos/aislamiento & purificación , Triterpenos/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/aislamiento & purificación , Apoptosis/efectos de los fármacos , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , ChinaRESUMEN
Neural networks based on low-power artificial synapses can significantly reduce energy consumption, which is of great importance in today's era of artificial intelligence. Two-dimensional (2D) material-based floating-gate transistors (FGTs) have emerged as compelling candidates for simulating artificial synapses owing to their multilevel and nonvolatile data storage capabilities. However, the low erasing/programming speed of FGTs renders them unsuitable for low-energy-consumption artificial synapses, thereby limiting their potential in high-energy-efficient neuromorphic computing. Here, we introduce a FGT-inspired MoS2/Trap/PZT heterostructure-based polarized tunneling transistor (PTT) with a simple fabrication process and significantly enhanced erasing/programming speed. Distinct from the FGT, the PTT lacks a tunnel layer, leading to a marked improvement in its erasing/programming speed. The PTT's highest erasing/programming (operation) speed can reach â¼20 ns, which outperforms the performance of most FGTs based on 2D heterostructures. Furthermore, the PTT has been utilized as an artificial synapse, and its weight-update energy consumption can be as low as 0.0002 femtojoule (fJ), which benefits from the PTT's ultrahigh operation speed. Additionally, PTT-based artificial synapses have been employed in constructing artificial neural network simulations, achieving facial-recognition accuracy (95%). This groundbreaking work makes it possible for fabricating future high-energy-efficient neuromorphic transistors utilizing 2D materials.
RESUMEN
OBJECTIVE: To review the operative technique of trephine arthrodesis of subtalar joints and evaluate its clinical effect. METHODS: From June 1998 to October 2006, we performed subtalar arthrodesis on 38 feet of 34 patients for a variety of painful disorders of hindfoot with trephine technique. Clinical and radiologic follow-up evaluations were performed for 45 months on average (range, 21 to 110 months) after arthrodesis. RESULTS: No severe complications were found in this study except one patient with dropfoot and two with skin necrosis. The average ankle-hindfoot scores of the American Orthopaedic Foot and Ankle Society (AOFAS) was improved from 48.3 preoperatively to 79.2 postoperatively (P<0.05). The pain scores of visual analogue scales (VAS) decreased from 7.2 (range, 3 to 10) preoperatively to 2.6 (range, 1 to 6) postoperatively (P<0.05). Subjectively, the patients experienced improvements in pain, function, cosmesis, and shoewearing. Overall, 30 patients were satisfied and all patients would have this procedure again under similar circumstances. Postoperative radiology showed that complete union was found in 35 feet 6 months after operation, with the successful union rate of 92.1%. There was an increase in arthritic scores for 5 ankles, 4 talonavicular joints, 4 calcaneocuboid joints, and 4 midfoot joints. Nonunion occurred in 3 subtalar joints with anterolateral approach, which required revision arthrodesis. CONCLUSION: Isolated subtalar arthrodesis with trephine method is an effective procedure for painful malalignment of hindfoot.
Asunto(s)
Artrodesis/métodos , Articulación Talocalcánea/cirugía , Adulto , Anciano , Artrodesis/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Dimensión del DolorRESUMEN
OBJECTIVE: To evaluate the practical method of vacuum sealing drainage (VSD) technique combined with sural neurovascular pedicle fasciocutaneous flap to repair deep wounds in the foot near the ankle joint with exposed bone and tendons. METHODS: From January 2006 to January 2009, 79 patients with deep wounds in the foot near the ankle joint with exposed bone and tendons were treated by VSD technique combined with sural neurovascular pedicle fasciocutaneous flap including 58 males and 21 females with an average age of 34 years old ranging from 7 to 59 years. There were 17 cases in low 1/3 part of leg and achilles tendon, 28 in lateral malleolus and lateral dorsum of foot, 21 in medial malleolus and medial dorsum of foot, 13 in heel and pelma. Firstly the wounds were debrided and cultivated by using VSD technique, then the soft tissue defections were repaired with sural neurovascular pedicle fasciocutaneous flap. RESULTS: The area of flap was from 6 cm x 5 cm to 18 cm x 15 cm; All patients stayed in hospital for 14 to 30 days, 18 days in average. Living flaps of all patients were followed-up from 6 months to 3 years, the flaps of 2 patients were mostly necrotic, 3 were necrotic, 5 cases appeared obstacle of venous back streaming. The others survived with no infections. CONCLUSION: The wound would become fresh and clean as soon as possible with VSD. The sural neurovascular pedicle fasciocutaneous flap could provide a good covering for the exposed wound. Therefore the wound healed faster with friction resistance and fine appearance. The time of hospitalization were greatly shortened after combined application.