JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Yi Yang,Weiwei Li,Yanjia Zhao,Hanqing Xu,Xu Wang,Guode Zhao,Zixia Hu,Ying Peng,Jiang Zheng
Dioscorea bulbifera L. is a traditional Chinese herb. As its principal active component, diosbulbin B (DSB) exhibits anticancer activity by inducing cell cycle arrest and apoptosis. Cell cycle progression relies on chromatin dynamics, which is regulated by histone post-translational modifications (PTMs). DSB is metabolized by CYP3A, resulting in the formation of a cis-enedial reactive intermediate (DDE) that selectively and covalently modifies lysine residues on histones, forming pyrroline derivatives, or in cooperation with glutathione (GSH), forming pyrrole derivatives. These modifications competitively disrupted canonical histone PTMs, accompanied by chromatin decompaction. The formation of these histone adductions and the alteration of histone PTM landscapes were validated in both mouse primary hepatocytes and Cyp3a4-HepG2 cells. Molecular dynamics simulations revealed that DDE-derived lysine adductions impair histone-DNA interactions. The observed covalent modification of histone lysine residues provides a novel strategy by regulating chromatin architecture and a conceptual framework for developing antitumor agents based on epigenetic mechanisms.
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高影响因子
Journal for ImmunoTherapy of Cancer
·
2024
·Vol. 12
·期 5
·e008662
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IF 10.3
Gan Xiong,Zhi Chen,Qianwen Liu,Fang Peng,Caihua Zhang,Maosheng Cheng,Rongsong Ling,Shuang Chen,Yu Liang,Demeng Chen,Qimin Zhou
Background CD276 (B7-H3), a pivotal immune checkpoint, facilitates tumorigenicity, invasiveness, and metastasis by escaping immune surveillance in a variety of tumors; however, the underlying mechanisms facilitating immune escape in esophageal squamous cell carcinoma (ESCC) remain enigmatic. Methods We investigated the expression of CD276 in ESCC tissues from patients by using immunohistochemistry (IHC) assays. In vivo, we established a 4-nitroquinoline 1-oxide (4NQO)-induced CD276 knockout (CD276 wKO ) and K14cre; CD276 conditional knockout (CD276 cKO ) mouse model of ESCC to study the functional role of CD276 in ESCC. Furthermore, we used the 4NQO-induced mouse model to evaluate the effects of anti-CXCL1 antibodies, anti-Ly6G antibodies, anti-NK1.1 antibodies, and GSK484 inhibitors on tumor growth. Moreover, IHC, flow cytometry, and immunofluorescence techniques were employed to measure immune cell proportions in ESCC. In addition, we conducted single-cell RNA sequencing analysis to examine the alterations in tumor microenvironment following CD276 depletion. Results In this study, we elucidate that CD276 is markedly upregulated in ESCC, correlating with poor prognosis. In vivo, our results indicate that depletion of CD276 inhibits tumorigenesis and progression of ESCC. Furthermore, conditional knockout of CD276 in epithelial cells engenders a significant downregulation of CXCL1, consequently reducing the formation of neutrophil extracellular trap networks (NETs) via the CXCL1–CXCR2 signaling axis, while simultaneously augmenting natural killer (NK) cells. In addition, overexpression of CD276 promotes tumorigenesis via increasing NETs’ formation and reducing NK cells in vivo. Conclusions This study successfully elucidates the functional role of CD276 in ESCC. Our comprehensive analysis uncovers the significant role of CD276 in modulating immune surveillance mechanisms in ESCC, thereby suggesting that targeting CD276 might serve as a potential therapeutic approach for ESCC treatment.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症生物学
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PubMed
高影响因子
ELECTROCHIMICA ACTA
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2025
·
IF 5.6
Chen Liu,Siwu Li,Lin Li,Qiyue Luo,Liang Ming,Ziling Jiang,Ziyu Lu,Miao Deng,Jie Yang,Shijie Cheng,Chuang Yu
The sulfide electrolyte-based all-solid-state batteries with high-nickel layered oxide cathodes face significant challenges due to the narrow electrochemical window of sulfides and severe side reactions caused by direct contact with high-voltage oxide cathode materials such as LiNi 0.9 Mn 0.05 Co 0.05 O 2 (NCM90). Here, we successfully synthesized Li 3 InCl 6 (LIC) halide electrolytes through ball-milling followed by annealing method, achieving the ionic conductivity of 2.0 mS cm −1 at room-temperature. The interface between this electrolyte and NCM90 cathode material without any interface modification is stable. By introducing the LIC electrolyte layer, the NCM90/LIC+Cl1.5/Li-In battery exhibits significantly improved electrochemical performance at different temperatures, particularly in terms of initial discharge capacity. Notably, the battery demonstrates outstanding discharge capacity and cycling stability at low temperatures. Experimental investigations reveal that the introduction of the LIC electrolyte with high oxidation potential facilitates the H2-H3 phase transition in NCM90 during high-voltage operation, which is critical for enhancing the discharge capacity. This work provides fundamental insights into interfacial engineering strategies for high-voltage sulfide-based all-solid-state battery systems.
研究领域:
储能
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材料科学
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电化学
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固态电池技术
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高影响因子
ACS Nano
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2024
·
IF 15.8
Dongyan Yu,Guifan Zeng,Diancheng Chen,Yawen Yan,Yue Zou,Qirui Liu,Kang Zhang,Kai Fang,Juping Xu,Wen Yin,Yu-Hao Hong,Tian Qiu,Hong-Gang Liao,Xiaoxiao Kuai,Yang Sun,Yu Qiao,Shi-Gang Sun
After charging to a high state-of-charge (SoC), layered oxide cathodes exhibit high capacities but suffer from gliding-induced structural distortions caused by deep Li depletion within alkali metal (AM) layers, especially for high-nickel candidates. In this study, we identify the essential structure of the detrimental H3 phase formed at high SoC to be an intergrowth structure characterized by random sequences of the O3 and O1 slabs, where the O3 slabs represent Li-rich layers and the O1 slabs denote Li-depleted (or empty) layers that glide from the O3 slabs. Moreover, we adopt two doping strategies targeting different doping sites to eliminate the formation of Li-vacant O1 slabs. First, we introduce direct transition metal (TM) pillars between TMO2 slabs achieved through dopants (e.g., Nb) positioned within AM layers, significantly improving the cycling stability. Second, we introduce indirect Li pillars achieved through dopants located at TM layers to adjust the Li–O bond strength. While this strategy can regulate the uniformity of Li at the slab level, it results in an uneven Li distribution at the particle scale, ultimately failing to enhance the electrochemical performance. Our established research strategy facilitates the realization of diverse pillars between TMO2 slabs through doping, thereby offering guidance for stabilizing high-capacity layered oxide cathodes at high SoC.
研究领域:
材料科学
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电化学
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电池技术
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
·
IF 6.2
Pan Song,Dong Lv,Luchen Yang,Jing Zhou,Xin Yan,Zhenghuan Liu,Kai Ma,Yunfei Yu,Xiaoyang Liu,Qiang Dong
Di-(2-ethylhexyl) phthalate (DEHP) might led to chronic and long-term effects on human organs due to its widespread use and bioaccumulation. Despite some cohorts reporting an association between DEHP exposure and BPH, its underlying mechanisms have not been investigated. Our findings indicate that exposure to DEHP or MEHP (main metabolites of DEHP in the human body) leads to increased prostate weights, elevated prostate index, and notable epithelial thickening in rats. It has been observed to promote BPH-1 cell proliferation with effects ranging from low to high concentrations. Transcriptome sequencing analysis of rat prostate tissues identified KIF11 as the key hub gene. KIF11 is highly expressed after DEHP/MEHP exposure, and knocking down of KIF11 inhibits the MEHP-induced promotion of cell proliferation. Exposure to MEHP has been observed to increase the expression of p-GSK-3β and elevate the levels of β-catenin, thereby activating the Wnt/β-catenin signaling pathway. Knocking down of KIF11 significantly inhibits these effects. Histone H3 at Lysine 27 acetylation (H3K27ac) is implicated in the upregulation of KIF11 expression, as evidenced by the addition of the acetylation inhibitor C646. In summary, our findings established that DEHP exposure could promote BPH through H3K27ac regulated KIF11/Wnt/β-catenin signaling pathway.
研究领域:
毒理学
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分子生物学
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内分泌学
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MOLECULAR PHARMACEUTICS
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2022
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IF 5.364
Lei Hou,Yunchang Zhang,Ying Huang,Zhen Fang,Guangze Sang,Tianheng Chen,Zhiqiang Ma,Feng Yang
Photodynamic therapy combined with chemotherapy is a promising strategy to improve the antitumor efficacy. On the basis of coupling the chlorin-based photosensitizer pyropheophorbide a (Pyro) and histone deacetylase inhibitors (HDACis) to fabricate dual-mode antitumor molecules, a series of dual-mode antitumor prodrug molecules were synthesized and assessed for antitumor activity in vitro and in vivo. The data demonstrated that compound 4, with the most favorable phototoxicity and dark toxicity, could significantly inhibit the cell migration and upregulate the expression of acetyl-H3 protein, functioning as a photosensitizer and HDACi, respectively. Furthermore, compared with talaporfin, Pyro, and SAHA, compound 4 demonstrated the best inhibitory effect on tumor growth and metastasis in tumor-bearing mice; therefore, represented by compound 4, this pharmacophore coupling strategy is much more promising and effective than the pharmacophore fusion strategy for fabricating photodynamic and chemotherapeutical dual-mode molecules.
研究领域:
药理学
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肿瘤学
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化疗
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光动力疗法
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药物设计
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高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2021
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IF 4.013
Lanqiu Zhang,Hejun Gao,Lei Yang,Tianyu Liu,Qi Zhang,Jing Xun,Caixia Li,Lihua Cui,Ximo Wang
FTY720 is an immunosuppressive agent which has been approved to treat multiple sclerosis (MS). The main object of the present study is to investigate whether FTY720 has the potential to induce the formation of neutrophil extracellular traps (NETs) in vitro. Using Sytox Green assay and fluorescence microscopy , our results showed that FTY720 trigged the NET formation. In contrast to classic NET formation induced by Phorbol 12-myristate 13-acetate (PMA), FTY720-induced NETs were detected earlier and independent of NADPH oxidase (NOX) activity. Pharmacological inhibitor experiments indicated that autophagy was also required for the NET formation induced by FTY720. Moreover, p38 and AKT inhibitor significantly suppressed the NET formation by FTY720, whereas ERK inhibitor had no effect, suggesting that FTY720-induced NETs depended on the activation of p38 and AKT. We further found that citrullination of histone H3 and peptidylarginine deiminase 4 (PAD4) did not mediated FTY720-induced NET formation. Interestingly, necroptosis signaling activation was involved in the vital NET formation by FTY720, however, plasma membrane rupture resulting from necroptosis was not a major component of NET formation described here. Collectively, these findings indicated that FTY720 could be a potential antibacterial drug to protect host against pathogen infection.
研究领域:
免疫学
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细胞生物学
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药理学
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高影响因子
JOURNAL OF PROTEOME RESEARCH
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2024
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IF 3.8
Chunyan Liu,Mengying Xu,Wan Li,Xiao Cao,Yan Wang,Haoran Chen,Tianqi Zhang,Meiyan Lu,Hui Xie,Yun Chen
Triple-negative breast cancer (TNBC) is known for its aggressive nature, and TNBC management is currently challenging due to the lack of effective targets. Despite the importance of histone post-translational modifications (hPTMs) in breast cancer, their associations with molecular subtypes of breast cancer, especially TNBC, are poorly understood. In this study, a combination of untargeted and targeted proteomics approaches, supplemented by a derivatization method, was applied to breast cancer cells and tissue samples. Untargeted proteomics of eight breast cancer cell lines belonging to different molecular subtypes revealed 36 modified peptides with 12 lysine modification sites in histone H3, and the most frequently reported top 5 histone H3 methylation and acetylation sites were covered. Then, targeted proteomics was carried out to quantify the total 20 target hPTMs at the covered modification sites (i.e., mono-, di-, trimethylation, and acetylation for each site), indicating the difficulty in distinguishing TNBC cells from normal cells. Subsequently, the analysis in TNBC patients revealed significant expression differences in 4 specific hPTMs (H3K14ac, H3K27me1, H3K36me2, and H3K36me3) between TNBC and adjacent normal tissue samples. These unique hPTM patterns allowed for the differentiation of TNBC from normal cases. This finding provides promising implications for advancing targeted treatment strategies for TNBC in the future.
研究领域:
癌症生物学
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蛋白质组学
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分子生物学
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临床肿瘤学
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高影响因子
Nano Energy
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2025
·
IF 17.1
Yujing Wu,Ziqi Zhang,Dengxu Wu,Fuqiang Xu,Mu Zhou,Hong Li,Liquan Chen,Fan Wu
Sulfide solid-state electrolytes (SEs), prized for high ionic conductivity and mechanical strength, face practical challenges due to multi-field coupling failures under operational stresses. While prior studies emphasize electrochemical degradation (e.g., interfacial reactions, Li dendrites), thermal failure mechanisms during high-temperature storage remain overlooked. This work systematically explores calendar aging in sulfide-based all-solid-state batteries (ASSBs). Among tested systems, LiCoO₂ (LCO), Li 6 PS 5 Cl, and Li-In alloy exhibit superior stability after high-temperature storage. However, high-voltage LiNi 0.8 Co 0.1 Mn 0.1 O₂ (NCM811) undergoes structural collapse, releasing decomposition products that accelerate interfacial reactions and thermal failure. Batteries at high states of charge (SOC) experience intensified self-discharge-driven electrode-electrolyte reactions at elevated temperatures. In contrast, LCO-Li 6 PS 5 Cl-LiIn ASSBs at 0 SOC retain nearly undegraded performance after 5 days at 90°C. Suppressing the detrimental H3-phase transition in NCM811 improves capacity retention by ≥21%. The study elucidates high-temperature degradation pathways in sulfide ASSBs, linking thermo-electro-chemical coupling effects to interfacial ion transport barriers and contact degradation. These insights advance the understanding of calendar aging mechanisms, providing critical guidance for predicting battery lifespan and designing robust electrode/electrolyte systems.
研究领域:
材料科学
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电化学
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储能
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电池技术
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热稳定性
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JOURNAL OF INVESTIGATIVE DERMATOLOGY
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2020
·
IF 7.143
Xiaoxuan Yu,Hui Li,Mengyuan Zhu,Po Hu,Xiao Liu,Yingjie Qing,Xiangyuan Wang,Hongzheng Wang,Zhanyu Wang,Jingyan Xu,Renxiang Tan,Qinglong Guo,Hui Hui
Cutaneous T-cell lymphomas (CTCLs) represent a rare form of non-Hodgkin lymphomas characterized by an accumulation of malignant CD4 + T cells in the skin. TP53 genetic alteration is one of the most prevalent genetic abnormalities in CTCLs. Therefore, it is a promising target for innovative therapeutic approaches. We found that p53 could physically interact with histone deacetylase (HDAC) 1 and HDAC8, and was subsequently deacetylated to lose its function in CTCL cells, and the p53 downstream apoptosis-associated genes were repressed. Thus, the anti-CTCL activity displayed by HDAC inhibitors depends on p53 status. However, recent studies have reported that HDAC inhibitors could induce a wide variety of drug-resistant characteristics in cancer cells by regulating ATP-binding cassette transporters. Moreover, we discovered that Baicalein, a natural product, exhibited an inhibitory effect on HDAC1 and HDAC8. Though the inhibition of HDAC1 was mild, Baicalein could induce the degradation of HDAC1 through the ubiquitin proteasome pathway, thereby markedly upregulating the acetylation of histone H3 without promoting ATP-binding cassette transporter gene expression. In terms of the mechanism, Baicalein showed better growth inhibition than traditional HDAC inhibitors in CTCLs. This study indicates a special mechanism of HDAC1 and HDAC8 and p53 in T-cell lymphoma cells and identifies a potential and safe natural HDAC inhibitor for the treatment of CTCLs.
研究领域:
肿瘤学
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分子生物学
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药理学
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免疫学
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PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Miao Jiefei,Meng Chi,Wu Hongmei,Shan Wenpei,Wang Haoran,Ling Changchun,Zhang Jinlin,Yang Tao
A novel hybrid CHC was designed and synthesized by conjugating β-carboline with an important active fragment N-hydroxyacrylamide of histone deacetylase (HDAC) inhibitor by an amide linkage to enhance antitumor efficacy/potency or even block drug resistance. CHC displayed high antiproliferative effects against drug-sensitive SUMM-7721, Bel7402, Huh7, and HCT116 cells and drug-resistant Bel7402/5FU cells with IC50 values ranging from 1.84 to 3.27 μM, which were two-to four-fold lower than those of FDA-approved HDAC inhibitor SAHA. However, CHC had relatively weak effect on non-tumor hepatic LO2 cells. Furthermore, CHC exhibited selective HDAC1/6 inhibitory effects and simultaneously augmented the acetylated histone H3/H4 and α-tubulin, which may make a great contribution to their antiproliferative effects. In addition, CHC also electrostatically interacted with CT-DNA, exerted remarkable cellular apoptosis by regulating the expression of apoptosis-related proteins and DNA damage proteins in Bel7402/5FU cells, and significantly accumulated cancer cells at the G2/M phase of the cell cycle by suppressing CDK1 and cyclin B protein with greater potency than SAHA-treated groups. Finally, CHC displayed strong inhibitory potency to drug-resistant hepatic tumors in mice. Our designed and synthetic hybrid CHC could be further developed as a significant and selective anticancer agent to potentially treat drug-resistant hepatocellular carcinoma.
研究领域:
药理学
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肿瘤学
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分子生物学
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PubMed
高影响因子
ADVANCED MATERIALS
·
2024
·
IF 27.4
Qingshuang Zou,Ke Liao,Guangchao Li,Xin Huang,Yongwei Zheng,Gun Yang,Min Luo,Evelyn Y. Xue,Chuanqing Lan,Shuai Wang,Yao Shen,Dixian Luo,Dennis K. P. Ng,Quan Liu
The infiltration and cytotoxicity of chimeric antigen receptor (CAR)-T cells are crucial for effective elimination of solid tumors. While metallo-immunotherapy is a promising strategy that can activate the antitumor immunity, its role in promoting CAR-T cell therapy remains elusive. The first single-element nanomaterial based on chromium nanoparticles (Cr NPs) for cancer photo-metallo-immunotherapy has been reported previously. Herein, an extended study using biodegradable polydopamine as a versatile carrier for these nanoparticles, enabling synergistic CAR-T cell therapy, is reported. The results show that these nanocomposites with or without further encapsulation of the anticancer drug alpelisib can promote the CAR-T cell migration and antitumor effect. Upon irradiation with near-infrared light, they caused mild hyperthermia that can “warm” the “cold” tumor microenvironment (TME). The administration of B7-H3 CAR-T cells to NOD severe combined immunodeficiency gamma mice bearing a human hepatoma or PIK3CA-mutated breast tumor can significantly inhibit the tumor growth after the induction of tumor hyperthermia by the nanocomposites and promote the secretion of serum cytokines, including IL-2, IFN-γ, and TNF-α. The trivalent Cr 3+ ions, which are the major degradation product of these nanocomposites, can increase the CXCL13 and CCL3 chemokine expressions to generate tertiary lymphoid structures (TLSs) in the tumor tissues, facilitating the CAR-T cell infiltration.
研究领域:
肿瘤学
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免疫疗法
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纳米技术
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生物医学工程
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癌症生物学
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高影响因子
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