Advanced Healthcare Materials
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2023
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IF 10
Wenhe Luo,Yanqiao Zeng,Qingle Song,Yu Wang,Feng Yuan,Qi Li,Yingnan Liu,Su Li,Nahar Jannatun,Guofang Zhang,Yang Li
Despite the success of immuno-oncology in clinical settings, the therapeutic efficacy is lower than the expectation due to the immunosuppressive inflammatory tumor microenvironment (TME) and the lack of functional lymphocytes caused by exhaustion. To enhance the efficacy of immuno-oncotherapy, a synergistic strategy should be used that can effectively improve the inflammatory TME and increase the tumor infiltration of cytotoxic T lymphocytes (CTLs). Herein, a TME hypoxia-responsive nanogel (NG) is developed to enhance the delivery and penetration of diacerein and (-)-epigallocatechin gallate (EGCG) in tumors. After systemic administration, diacerein effectively improves the tumor immunosuppressive condition through a reduction of MDSCs and Tregs in TME, and induces tumor cell apoptosis via the inhibition of IL-6/STAT3 signal pathway, realizing a strong antitumor effect. Additionally, EGCG can effectively inhibit the expression of PD-L1, restoring the tumor-killing function of CTLs. The infiltration of CTLs increases at the tumor site with activation of systemic immunity after the combination of TIM3 blockade therapy, ultimately resulting in a strong antitumor immune response. This study provides valuable insights for future research on eliciting effective antitumor immunity by suppressing adverse tumor inflammation. The feasible strategy proposed in this work may solve the urgent clinical concerns of the dissatisfactory checkpoint-based immuno-oncotherapy.
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Advanced Healthcare Materials
·
2023
·
IF 10
Dengjie Yu,Qingbin Nie,Jiangtao Xue,Ruizeng Luo,Shiwang Xie,Shengyu Chao,Engui Wang,Linlin Xu,Yizhu Shan,Zhuo Liu,Yusheng Li,Zhou Li
Osteoarthritis (OA) is the most prevalent joint degenerative disease characterized by chronic joint inflammation. The pathogenesis of OA has not been fully elucidated yet. Cartilage erosion is the most significant pathological feature in OA, which is considered as the result of the cytomechanical homeostasis destruction. The cytomechanical homeostasis is maintained by the dynamic interaction between cells and the extracellular matrix, which can be reflected by cell traction force (CTF). It is critical to assess the CTF for providing a deeper understanding of the cytomechanical homeostasis destruction and progression in OA. In this study, a silicon nanopillar array (Si-NP) with high spatial resolution and aspect ratio is fabricated to investigate the CTF in response to OA. We discover the CTF is degraded in OA, which is attributed to the F-actin reorganization induced by the activation of RhoA/ROCK signaling pathway. Si-NP also show promising potential as a mechanopharmacological assessment platform for OA drug screening and evaluation. This article is protected by copyright. All rights reserved
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ANALYTICAL CHEMISTRY
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2020
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IF 6.785
Yan Zhang,Qing-nan Li,Kaiyue Zhou,Qinfeng Xu,Chun-yang Zhang
The fat mass and obesity-associated enzyme (FTO) can catalyze the demethylation of N6-methyladenosine (m6A) residues in mRNA, regulates the cellular level of m6A modification, and plays a critical role in human obesity and cancers. Herein, we develop a single-quantum-dot (QD)-based fluorescence resonance energy transfer (FRET) sensor for the identification of specific FTO demethylase inhibitors. The FTO-mediated demethylation of m6A can induce the cleavage of demethylated DNA to generate the biotinylated DNA fragments, which may function as capture probes to assemble the Cy5-labeled reporter probes onto the QD surface, enabling the occurrence of FRET between the QD and Cy5. The presence of inhibitors can inhibit the FTO demethylation and consequently abolish FRET between the QD and Cy5. The inhibition effect of inhibitors upon FTO demethylation can be simply evaluated by monitoring the decrease of Cy5 counts. We use this nanosensor to screen several small-molecule inhibitors and identify diacerein as a highly selective inhibitor of FTO. Diacerein can inhibit the demethylation activity of endogenous FTO in HeLa cells. Interestingly, diacerein is neither a structural mimic of 2-oxoglutarate (2-OG) nor a chelator of metal ions, and it can selectively inhibit FTO demethylation by competitively binding the m6A-containing substrate.
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Acta Pharmaceutica Sinica B
·
2024
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IF 14.7
Li Qiao,Zhiyao Li,Bowen Li,Fu Zhang,Zhuo Yao,Chongzhi Wu,Honglin Tang,Qi Pan,Peihua Shi,Yuan Ping
Osteoarthritis (OA) is a type of highly prevalent heterogeneous degenerative disease that leads to joint pain, deformity, the destruction of articular cartilage, and eventual disability. The current treatment strategies for OA often suffer from systemic side effects, poor anti-inflammatory efficacy, and persistent pain. To address these issues, we develop light-inducible nanomedicine that enables the co-delivery of anti-inflammatory drug (diacerein, DIA) and small interfering RNA (siRNA) targeting nerve growth factor (NGF) for pain relief to enhance the therapeutic efficacy of OA. The nanomedicine is based on poly( β -amino-ester)-coated gold nanocages (AuNCs), which is further incorporated with the phase-change material (lauric acid/stearic acid, LA/SA). Following intra-articular (IA) injection in vivo , the nanomedicine displays high degree of drug accumulation and retention in the joint lesion of OA mouse models. The photothermal effect, induced by AuNCs, not only promotes DIA and siRNA release, but also upregulates the expression of heat shock protein 70 (HSP-70) to resist the apoptosis of chondrocytes in the inflammatory condition. The internalization of both DIA and siRNA results in strong anti-inflammatory and pain-relieving effects, which greatly contribute to the joint repair of OA mice. This study offers a promising combination strategy for OA treatment.
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