AbstractMany species are threatened by climate change and must rapidly respond to survive in changing environments. Epigenetic modifications, such as DNA methylation, can facilitate plastic responses by regulating gene expression in response to environmental cues. Understanding epigenetic responses is therefore essential for predicting species' ability to rapidly adapt in the context of global environmental change. Here, we investigated the functional significance of different methylation‐associated cellular processes on temperature‐dependent life history in seed beetles, Callosobruchus maculatus Fabricius 1775 (Coleoptera: Bruchidae). We assessed changes under thermal stress in (1) DNA methyltransferase (Dnmt1 and Dnmt2) expression levels, (2) genome‐wide methylation and (3) reproductive performance, with (2) and (3) following treatment with 3‐aminobenzamide (3AB) and zebularine (Zeb) over two generations. These drugs are well‐documented to alter DNA methylation across the tree of life. We found that Dnmt1 and Dnmt2 were expressed throughout the body in males and females, but were highly expressed in females compared with males and exhibited temperature dependence. However, whole‐genome methylation did not significantly vary with temperature, and only marginally or inconclusively with drug treatment. Both 3AB and Zeb led to profound temperature‐dependent shifts in female reproductive life history trade‐off allocation, often increasing fitness compared with control beetles. Mismatch between magnitude of treatment effects on DNA methylation versus life history effects suggest potential of 3AB and Zeb to alter reproductive trade‐offs via changes in DNA repair and recycling processes, rather than or in addition to (subtle) changes in DNA methylation. Together, our results suggest that epigenetic mechanisms relating to Dnmt expression, DNA repair and recycling pathways, and possibly DNA methylation, are strongly implicated in modulating insect life history trade‐offs in response to temperature change.

2024-08-06·ACS Nano

Ultrasound-Activatable In Situ Vaccine for Enhanced Antigen Self- and Cross-Presentation to Overcome Cancer Immunotherapy Resistance

Article

作者: Yang, Siyi ; Zhang, Beibei ; Li, Ruifang ; Mo, Lianfeng ; Huang, Rong ; Chen, Ge ; Wang, Yongchao ; Zhang, Lianzhong ; Xu, Xiaoxia ; Zhang, Xu

Insufficient antigen self-presentation of tumor cells and ineffective antigen cross-presentation by dendritic cells (DCs) contribute to diminished immune recognition and activation, which cause resistance to immunotherapies. Herein, we present an ultrasound-activatable in situ vaccine by utilizing a hybrid nanovesicle composed of a thylakoid (TK)/platelet (PLT) membrane and a liposome encapsulating DNA methyltransferase inhibitor zebularine (Zeb) and sonosensitizer hematoporphyrin monomethyl ether (HMME). Upon local exposure to ultrasound, reactive oxygen species (ROS) are generated and induce the sequential release of the payloads. Zeb can efficiently inhibit tumor DNA hypermethylation, promoting major histocompatibility complex class I (MHC-I) molecules-mediated antigen self-presentation to improve immune recognition. Meanwhile, the catalase on the TK membrane can decompose the tumoral overexpressed H₂O₂ into O₂, which boosts the generation of ROS and the destruction of tumor cells, resulting in the in situ antigen release and cross-presentation of tumor antigens by DCs. This in situ vaccine simultaneously promotes antigen self-presentation and cross-presentation, resulting in heightened antitumor immunity to overcome resistance.

2024-03-01·Advanced Science

Nano‐Regulator Inhibits Tumor Immune Escape via the “Two‐Way Regulation” Epigenetic Therapy Strategy

Article

作者: Liang, Shuang ; Jiang, Dandan ; Yuan, Shijun ; Fu, Shunli ; Liu, Meichen ; Gao, Shuying ; Zhang, Na ; Liu, Jinhu ; Mu, Weiwei ; Liu, Yongjun ; Gao, Tong

AbstractTumor immune escape caused by low levels of tumor immunogenicity and immune checkpoint‐dependent suppression limits the immunotherapeutic effect. Herein, a “two‐way regulation” epigenetic therapeutic strategy is proposed using a novel nano‐regulator that inhibits tumor immune escape by upregulating expression of tumor‐associated antigens (TAAs) to improve immunogenicity and downregulating programmed cell death 1 ligand 1 (PD‐L1) expression to block programmed death‐1 (PD‐1)/PD‐L1. To engineer the nano‐regulator, the DNA methyltransferase (DNMT) inhibitor zebularine (Zeb) and the bromodomain‐containing protein 4 (BRD4) inhibitor JQ1 are co‐loaded into the cationic liposomes with condensing the toll‐like receptor 9 (TLR9) agonist cytosine‐phosphate‐guanine (CpG) via electrostatic interactions to obtain G‐J/ZL. Then, asparagine–glycine–arginine (NGR) modified material carboxymethyl‐chitosan (CMCS) is coated on the surface of G‐J/ZL to construct CG‐J/ZL. CG‐J/ZL is shown to target tumor tissue and disassemble under the acidic tumor microenvironment (TME). Zeb upregulated TAAs expression to improve the immunogenicity; JQ1 inhibited PD‐L1 expression to block immune checkpoint; CpG promote dendritic cell (DC) maturation and reactivated the ability of tumour‐associated macrophages (TAM) to kill tumor cells. Taken together, these results demonstrate that the nano‐regulator CG‐J/ZL can upregulate TAAs expression to enhance T‐cell infiltration and downregulate PD‐L1 expression to improve the recognition of tumor cells by T‐cells, representing a promising strategy to improve antitumor immune response.

100 项与 ZEB antagonists (CD3) 相关的药物交易

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