Metallic zinc anodes of aqueous zinc ion batteries suffer from severe dendrite and side reaction issues, resulting in poor cycling stability, especially at high rates and capacities. Herein, we ...develop two three-dimensional hierarchical graphene matrices consisting of nitrogen-doped graphene nanofibers clusters anchored on vertical graphene arrays of modified multichannel carbon. The graphene matrix with radial direction carbon channels possesses high surface area and porosity, which effectively minimizes the surface local current density, manipulates the Zn
ions concentration gradient, and homogenizes the electric field distribution to regulate Zn deposition. As a result, the engineered matrices achieve a superior coulombic efficiency of 99.67% over 3000 cycles at 120 mA cm
, the symmetric cells with the composite zinc anode demonstrates 2600 h dendrite-free cycles at 80 mA cm
and 80 mAh cm
. The as-designed full cell exhibits an inspiring capacity of 16.91 mAh cm
. The Zn capacitor matched with activated carbon shows a superior long-term cycle performance of 20000 cycles at 40 mA cm
. This strategy of constructing a 3D hierarchical structure for Zn anodes may open up a new avenue for metal anodes operating under high rates and capacities.
Carbon quantum dots (CQDs) offer huge potential due to their enzymatic properties as compared to natural enzymes. Thus, discovery of CQDs-based nanozymes with low toxicity from natural resources, ...especially daily food, implies a promising direction for exploring treatment strategies for human diseases. Here, we report a CQDs-based biocompatible nanozyme prepared from chlorogenic acid (ChA), a major bioactive natural product from coffee. We found that ChA CQDs exhibited obvious GSH oxidase-like activities and subsequently promoted cancer cell ferroptosis by perturbation of GPX4-catalyzed lipid repair systems. In vivo, ChA CQDs dramatically suppressed the tumor growth in HepG2-tumor-bearing mice with negligible side toxicity. Particularly, in hepatoma H22-bearing mice, ChA CQDs recruited massive tumor-infiltrating immune cells including T cells, NK cells, and macrophages, thereby converting “cold” to “hot” tumors for activating systemic antitumor immune responses. Taken together, our study suggests that natural product-derived CQDs from coffee can serve as biologically safe nanozymes for anticancer therapeutics and may aid the development of nanotechnology-based immunotherapeutic.
Syndecan-4 (SDC4) functions as a major endogenous membrane-associated receptor and widely regulates cytoskeleton, cell adhesion, and cell migration in human tumorigenesis and development, which ...represents a charming anti-cancer therapeutic target. Here, SDC4 was identified as a direct cellular target of small-molecule bufalin with anti-hepatocellular carcinoma (HCC) activity. Mechanism studies revealed that bufalin directly bond to SDC4 and selectively increased SDC4 interaction with substrate protein DEAD-box helicase 23 (DDX23) to induce HCC genomic instability. Meanwhile, pharmacological promotion of SDC4/DDX23 complex formation also inactivated matrix metalloproteinases (MMPs) and augmented p38/JNK MAPKs phosphorylation, which are highly associated with HCC proliferation and migration. Notably, specific knockdown of SDC4 or DDX23 markedly abolished bufalin-dependent inhibition of HCC proliferation and migration, indicating SDC4/DDX23 signaling axis is highly involved in the HCC process. Our results indicate that membrane-spanning proteoglycan SDC4 is a promising druggable target for HCC, and pharmacological regulation of SDC4/DDX23 signaling axis with small-molecule holds great potential to benefit HCC patients.
Antimony selenide (Sb2Se3) is a highly promising photovoltaic material thanks to its outstanding optoelectronic properties, as well as its cost‐effective and eco‐friendly merits. However, toxic CdS ...is widely used as an electron transport layer (ETL) in efficient Sb2Se3 solar cells, which largely limit their development toward market commercialization. Herein, an effective green Cd‐free ETL of SnOx is introduced and deposited by atomic layer deposition method. Additionally, an important post‐annealing treatment is designed to further optimize the functional layers and the heterojunction interface properties. Such engineering strategy can optimize SnOx ETL with higher nano‐crystallinity, higher carrier density, and less defect groups, modify Sb2Se3/SnOx heterojunction with better interface performance and much desirable “spike‐like” band alignment, and also improve the Sb2Se3 light absorber layer quality with passivated bulk defects and prolonged carrier lifetime, and therefore to enhance carrier separation and transport while suppressing non‐radiative recombination. Finally, the as‐fabricated Cd‐free Mo/Sb2Se3/SnOx/ITO/Ag thin‐film solar cell exhibits a stimulating efficiency of 7.39%, contributing a record value for Cd‐free substrate structured Sb2Se3 solar cells reported to date. This work provides a viable strategy for developing and broadening practical applications of environmental‐friendly Sb2Se3 photovoltaic devices.
Actomic layer deposition processed SnOx is introduced as electron transport layer in Sb2Se3 thin‐film solar cells. An additional post‐annealing can remarkably enhance the photovoltaic performance, thanks to the optimized carrier dynamics under simultaneously improving the properties of SnOx, Sb2Se3/SnOx heterojunction and Sb2Se3 absorber layer. A stimulating efficiency of 7.39% represents the record value for Cd‐free substrate structured Sb2Se3 solar cells.
Immune checkpoint blockade resistance narrows the efficacy of cancer immunotherapies, but the underlying mechanism remains elusive. Delineating the inherent mechanisms of anti-PD1 resistance is ...important to improve outcome of patients with advanced HCC.
The level of cricTMEM181 was measured in HCC patients with anti-PD1 therapy by RNA sequencing and then confirmed by qPCR and Sanger sequencing. Immune status in tumor microenvironment of HCC patients or mice models was evaluated by flow cytometry and IHC. Exosomes from HCC cell lines were isolated by ultracentrifugation, and their internalization by macrophage was confirmed by immunofluorescence. The underlying mechanism of HCC-derived exosomal circTMEM181 to macrophage was confirmed by SILAC, RNA FISH and RNA immunoprecipitation. The ATP-ADO pathway amplified by HCC-macrophage interaction was evaluated through ATP, AMP and ADO measurement and macrophage-specific CD39 knockout mice. The role of circTMEM181 in anti-PD1 therapy and its clinical significance were also determined in our retrospective HCC cohorts.
Here, we found that circTMEM181 was elevated in hepatocellular carcinoma (HCC) patients responding poorly to anti-PD1 therapy and in HCC patients with a poor prognosis after operation. Moreover, we also found that high exosomal circTMEM181 favored the immunosuppressive microenvironment and endowed anti-PD1 resistance in HCC. Mechanistically, exosomal circTMEM181 sponged miR-488-3p and upregulated CD39 expression in macrophages. Using macrophage-specific CD39 knockout mice and pharmacologic approaches, we revealed a novel mode of anti-PD1 resistance in HCC. We discovered that cell-specific CD39 expression in macrophages and CD73 expression in HCC cells synergistically activated the eATP-adenosine pathway and produced more adenosine, thereby impairing CD8
T cell function and driving anti-PD1 resistance.
In summary, HCC-derived exosomal circTMEM181 contributes to immunosuppression and anti-PD1 resistance by elevating CD39 expression, and inhibiting the ATP-adenosine pathway by targeting CD39 on macrophages can rescue anti-PD1 therapy resistance in HCC.
The aim of this study was to investigate the correlation between Silva pattern system and clinicopathological features of endocervical adenocarcinoma. Moreover, it was to find molecular markers ...helpful for Silva classification, and thus we also explored the expression levels of invasion, adhesion and proliferation biomarkers in cases of Silva non‐invasive and invasive types. The survival based on Silva pattern system was analysed by Kaplan–Meier survival analysis, Log‐rank test and a COX risk proportionality model. Sixty samples were chosen to detect the MMP‐2, MMP‐9, u‐PA, E‐cadherin, β‐catenin, EGF, TGF‐α, HDGF, c‐Met and RGN expression by immunohistochemistry. Multivariate analysis showed that pattern A/pattern B/pattern C Silva pattern system provided independent risk factors for prognosis. Our results found the levels of MMP‐2, MMP‐9 and u‐PA were significantly higher in endocervical adenocarcinoma with destructive growth than in the nondestructive group. The levels of E‐cadherin and β‐catenin were significantly lower in endocervical adenocarcinoma with destructive growth than in the nondestructive group. The levels of EGF, TGF‐α and HDGF were significantly higher in endocervical adenocarcinoma with destructive growth than in the nondestructive group. Compared with ‘non‐invasive/invasive Silva pattern’, this study suggests ‘pattern A/pattern B/pattern C Silva pattern’ could be a better criteria for predicting the prognosis. Furthermore, the dual‐marker combination of ‘MMP‐2 and u‐PA’ and ‘E‐cadherin and β‐catenin’ is very important in the diagnosis of Silva pattern classification.
Understanding the direct interaction of nanostructures per se with biological systems is important for biomedical applications. However, whether nanostructures regulate biological systems by ...targeting specific cellular proteins remains largely unknown. In the present work, self‐assembling nanomicelles are constructed using small‐molecule oleanolic acid (OA) as a molecular template. Unexpectedly, without modifications by functional ligands, OA nanomicelles significantly activate cellular proteasome function by directly binding to 20S proteasome subunit alpha 6 (PSMA6). Mechanism study reveals that OA nanomicelles interact with PSMA6 to dynamically modulate its N‐terminal domain conformation change, thereby controlling the entry of proteins into 20S proteasome. Subsequently, OA nanomicelles accelerate the degradation of several crucial proteins, thus potently driving cancer cell pyroptosis. For translational medicine, OA nanomicelles exhibit a significant anticancer potential in tumor‐bearing mouse models and stimulate immune cell infiltration. Collectively, this proof‐of‐concept study advances the mechanical understanding of nanostructure‐guided biological effects via their inherent capacity to activate proteasome.
Self‐assembling nanomicelles constructed by small‐molecule oleanolic acid (OA) significantly activate cellular proteasome function by directly binding to 20S proteasome subunit alpha 6 (PSMA6). Mechanistically, OA nanomicelles interact with PSMA6 to dynamically modulate its N‐terminal domain conformation change, thereby controlling the entry of proteins into 20S proteasome, thus accelerating the degradation of several crucial proteins and driving cancer cell pyroptosis.
Neuroinflammation is initiated in response to a variety of endogenous and exogenous sources. As the resident macrophages of the central nervous system, the polarization of microglia into either the ...M1 pro-inflammatory phenotype or the M2 anti-inflammatory phenotype holds great promise as a therapeutic strategy for neuroinflammation. Natural products, comprising a vital chemical library with distinctive structures and diverse functions, have been extensively employed to modulate microglial polarization for the treatment of neuroinflammation. In this review, we present up-to-date and extensive insights into the therapeutic effects and underlying mechanisms of natural products in the context of neuroinflammation. Furthermore, the review aims to present a new perspective by focusing on the targets of natural compounds, elucidating the molecular mechanisms and guiding the transition from natural-derived lead compounds to potential anti-neuroinflammatory drugs. Additionally, we provide a comprehensive overview of the challenges and limitations associated with the utilization of natural products for neuroinflammation therapy.
Protopanaxadiol (PPD), a main ginseng metabolite, exerts powerful anticancer effects against multiple types of cancer; however, its cellular targets remain elusive. Here, we synthesized a ...cell‐permeable PPD probe via introducing a bifunctional alkyne‐containing diazirine photo‐crosslinker and performed a photoaffinity labeling‐based chemoproteomic study. We identified retinoblastoma binding protein 4 (RBBP4), a chromatin remodeling factor, as an essential cellular target of PPD in HCT116 colorectal cancer cells. PPD significantly decreased RBBP4‐dependent trimethylation at lysine 27 of histone H3 (H3K27me3), a crucial epigenetic marker that correlates with histologic signs of colorectal cancer aggressiveness, and PPD inhibition of proliferation and migration of HCT116 cells was antagonized by RBBP4 RNA silencing. Collectively, our study highlights a previously undisclosed anti‐colorectal cancer cellular target of the ginseng metabolite and advances the fundamental understanding of RBBP4 functions via a chemical biology strategy.
HCT116 cells were treated with the cell permeable probe AD‐PPD, and irradiated with UV in situ. Labelled proteomes were further conjugated to biotin‐PEG3‐azide via click chemistry, and the target of protopanaxadiol (PPD) was identified as RBBP4 by LC‐MS/MS analysis.
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