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Ta-doped Li7La3Zr2O12 (LLZTO) solid-state electrolytes (SEs) show great promise for solid-state batteries due to its high conductivity and safety. However, one of the challenges it faces is lithium dendrite propagation upon long-term cycling. To address this issue, we propose the incorporation of fumed silica (FS) at the grain boundaries of LLZTO to modify the properties of the garnet pellet, which effectively inhibits the dendrite growth. The introduction of FS has demonstrated several beneficial effects. Firstly, it reduces the migration barrier of lithium ions, which helps prevent dendrite formation and propagation. Additionally, FS reduces the electronic conductivity of the SEs pellet, suppressing the dendrite formation. Moreover, the formed lithium silicates from FS might also be acted as electron inhibitor, thus inhibiting the lithium dendrite growth upon cycling. By investigating the use of FS as a modifier in LLZTO-based electrolytes, our study contributes to advancing dendrite-free solid-state electrolytes and thus the development of high-performance all-solid-state batteries.
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Although recombinant human TNF-related apoptosis-inducing ligand (TRAIL) protein exhibits antitumor activity in a number of lung and liver cancer cells and tumor-bearing animals, TRAIL resistance has substantially restricted its clinical application. Pyrroline-5-carboxylate reductase 1 (PYCR1) is a key enzyme in the regulation of proline synthesis. PYCR1 is highly expressed in various types of malignant tumor, in which it has been implicated in 5-fluorouracil resistance. However, the possible relationship between PYCR1 and TRAIL resistance remains unclear. In the present study, both reverse transcription-quantitative PCR and western blotting were performed. The results indicated that H1299 cells had higher PYCR1 expression levels and were less sensitive to TRAIL compared with the TRAIL-sensitive cell line, H460. PYCR1 knockdown in H1299 cells increased TRAIL sensitivity, increased the localization of death receptors (DRs) on the cell surface and activated Caspase-3/8. By contrast, overexpression of PYCR1 in H1299 cells decreased TRAIL sensitivity, reduced the distribution of DRs on the cell surface and suppressed the activation of Caspase-3/8. Taken together, these results suggested that PYCR1 promoted TRAIL resistance in the non-small cell lung cancer cell line, H1299, by preventing redistribution of DRs to the plasma membrane. This in turn inhibited TRAIL-mediated cell apoptosis by reducing the activation of Caspase-3/8.
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The blood-spinal cord barrier (BSCB) plays a vital role in the recovery of spinal cord function after spinal cord injury (SCI). Pericytes, pluripotent members of the neurovascular unit (NVU), receive signals from neighboring cells and are critical for maintaining CNS function. Therapeutic targets for the BSCB include endothelial cells (ECs) and glial cells, but few drugs target pericytes. This study was designed to explore whether asiaticoside has a positively effect on pericytes and the integrity of the BSCB. In this study, we found that asiaticoside could inhibit the loss of junction proteins just 1 day after SCI in vivo, but our in vitro study showed no significant differences in the expression of endothelial junction proteins between the control and asiaticoside treatment groups. We also found that asiaticoside could inhibit endoplasmic reticulum (ER) stress and pericyte apoptosis, which might be associated with the inhibition of junction protein reduction in ECs. Thus, we investigated the interactions between pericytes and ECs. Our results showed that asiaticoside could decrease the release of matrix metalloproteinase (MMP)-9 in pericytes and therefore upregulate the expression of junction proteins in ECs. Furthermore, the protective effect of asiaticoside on pericytes is related to the inhibition of ER stress via the MAPK signaling pathway. Taken together, our results demonstrate that asiaticoside treatment inhibits BSCB disruption and enhances functional recovery after SCI.
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Pericitos , Traumatismos de la Médula Espinal , Triterpenos , Ratas , Animales , Humanos , Pericitos/metabolismo , Células Endoteliales/metabolismo , Ratas Sprague-Dawley , Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Barrera Hematoencefálica/metabolismo , Estrés del Retículo EndoplásmicoRESUMEN
Osteoporosis, characterized by over-production and activation of osteoclasts, has become a major health problem especially in elderly women. In our study, we first tested the effect of Caudatin (Cau) in osteoclastogenesis, which is separated from Cynanchum auriculatum as a species of C-21 steroidal glyosides. The results indicated that Cau suppressed osteoclastogenesis in a time- and dose-dependent manner in vitro. Mechanistically, Cau was identified to inhibit NF-κB signaling pathway via modulation of KIF11-mediated mTORC1 activity. In vivo, by establishing an ovariectomized (OVX) mouse model to mimic osteoporosis, we confirmed that Cau treatment prevented OVX-induced bone loss in mice. In conclusion, we demonstrated that Cau inhibited NF-κB signaling pathway via modulation of KIF11-mediated mTORC1 activity to suppress osteoclast differentiation in vitro as well as OVX-induced bone loss in vivo. This provides the possibility of a novel prospective drug for osteoporosis remedies.
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Resorción Ósea , Osteoporosis , Animales , Ratones , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/prevención & control , Resorción Ósea/metabolismo , Diferenciación Celular , Cinesinas/metabolismo , FN-kappa B/metabolismo , Osteoclastos , Osteogénesis , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & control , Osteoporosis/metabolismo , Ovariectomía , Ligando RANK/farmacología , Transducción de Señal , Diana Mecanicista del Complejo 1 de la RapamicinaRESUMEN
The cell membrane structure is closely related to the occurrence and progression of many metabolic bone diseases observed in the clinic and is an important target to the development of therapeutic strategies for these diseases. Strong experimental evidence supports the existence of membrane microdomains in osteoclasts (OCs). However, the potential membrane microdomains and the crucial mechanisms underlying their roles in OCs have not been fully characterized. Membrane microdomain components, such as scaffolding proteins and the actin cytoskeleton, as well as the roles of individual membrane proteins, need to be elucidated. In this review, we discuss the compositions and critical functions of membrane microdomains that determine the biological behavior of OCs through the three main stages of the OC life cycle.
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Proteínas de la Membrana , Osteoclastos , Proteínas de la Membrana/metabolismo , Microdominios de Membrana/metabolismo , Estructuras de la Membrana Celular/metabolismoRESUMEN
Hypocrellins (HYPs) are natural perylene quinone derivatives from Ascomycota fungi. Based on the excellent photosensitization properties of HYPs, this work proposed a photocatalytic advanced oxidation process (PAOP) that uses HYPs to degrade rhodamine B (RhB) as a model organic pollutant. A synergistic activity of HYPs and H2O2 (0.18 mM of HYPs, 0.33% w/v of H2O2) was suggested, resulting in a yield of 82.4% for RhB degradation after 60 min under visible light irradiation at 470−475 nm. The principle of pseudo-first-order kinetics was used to describe the decomposition reaction with a calculated constant (k) of 0.02899 min−1 (R2 = 0.983). Light-induced self-degradation of HYPs could be activated under alkaline (pH > 7) conditions, promising HYPs as an advanced property to alleviate the current dilemma of secondary pollution by synthetic photocatalysts in the remediation of emerging organic pollutants.
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Location and properties of ligand binding sites provide important information to uncover protein functions and to direct structure-based drug design approaches. However, as binding site detection depends on the three-dimensional (3D) structural data of proteins, functional analysis based on protein ligand binding sites is formidable for proteins without structural information. Recent developments in protein structure prediction and the 3D structures built by AlphaFold provide an unprecedented opportunity for analyzing ligand binding sites in human proteins. Here, we constructed the CavitySpace database, the first pocket library for all the proteins in the human proteome, using a widely-applied ligand binding site detection program CAVITY. Our analysis showed that known ligand binding sites could be well recovered. We grouped the predicted binding sites according to their similarity which can be used in protein function prediction and drug repurposing studies. Novel binding sites in highly reliable predicted structure regions provide new opportunities for drug discovery. Our CavitySpace is freely available and provides a valuable tool for drug discovery and protein function studies.
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Proteoma , Sitios de Unión , Fenómenos Biofísicos , Humanos , Ligandos , Unión ProteicaRESUMEN
Osteoporosis a common disease in postmenopausal women which contains significant impact on the living quality of women. With the aging of the population, the number of patients suffer from osteoporosis has shown a significant increase. Given the limitations of clinical drugs for the treatment of osteoporosis, natural extracts with small side effects have a great application prospect in the treatment of osteoporosis. Praeruptorin B (Pra-B), is one of the main components found in the roots of Peucedanum praeruptorum Dunn and exhibits anti-inflammatory effects. However, there is no research on the influence of Pra-B on osteoporosis. Here, we showed that Pra-B can dose-dependently suppress osteoclastogenesis without cytotoxicity. Receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL)-induced the nuclear import of P65 was inhibited by Pra-B, which indicated the suppressive effect of Pra-B on NF-κB signaling. Further, Pra-B enhanced the expression of Glutathione S-transferase Pi 1 (GSTP1) and promoted the S-glutathionylation of IKKß to inhibit the nuclear translocation of P65. Moreover, in vivo experiments showed that Pra-B considerably attenuated the bone loss in ovariectomy (OVX)-induced mice. Collectively, our studies revealed that Pra-B suppress the NF-κB signaling targeting GSTP1 to rescued RANKL-induced osteoclastogenesis in vitro and OVX-induced bone loss in vivo, supporting the potential of Pra-B for treating osteoporosis in the future.