JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Yahui Huang,Na Liu,Zhizhi Pan,Zhuang Li,Chunquan Sheng
Breast cancer is susceptible to Candida infections, and candidiasis has an enhancing effect on the progression and metastasis of tumor. Breast cancer and concurrent candidiasis represent a significant challenge in clinical therapy. Herein, a series of novel small molecule inhibitors simultaneously targeting bromodomain and extra-terminal (BET) and histone deacetylase (HDAC) were designed for combinational treatment of breast cancer and resistant Candida albicans infections. Among them, compounds 13c and 17b exhibited excellent and balanced inhibitory activity against both BET family proteins BRD4 and HDAC1. As compared with BRD4 or HDAC1 inhibitors, dual inhibitors 13c and 17b displayed improved in vivo antitumor efficacy in MDA-MB-231 breast cancer xenograft models. Notably, they synergized with fluconazole (FLC) to effectively reduce the kidney fungal burden in a murine model of disseminated candidiasis. Thus, the BET–HDAC dual inhibitors represented a novel therapeutic strategy for combinational treatment of breast cancer and concurrent candidiasis.
研究领域:
肿瘤学
·
医学微生物学
·
药物化学
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DOI
PubMed
高影响因子
CANCER RESEARCH
·
2024
·
IF 12.5
Qiang Yulong,Fan Jiachen,Xie Chuanshuai,Yan Leilei,Song Xiaofei,Zhang Nan,Lin Yan,xiong jie,Zhang Wei,Liu Yu,Wei Lei,Li Yu,Chen Shizhen,Liang Kaiwei,Li Feng
The BET family member BRD4 is a bromodomain-containing protein that plays a vital role in driving oncogene expression. Given their pivotal role in regulating oncogenic networks in various cancer types, BET inhibitors (BETis) have been developed, but the clinical application has been impeded by dose-limiting toxicity and resistance. Understanding the mechanisms of BRD4 activity and identifying predictive biomarkers could facilitate the successful clinical use of BETis. Herein, we showed that KDM5C and BRD4 cooperate to sustain tumor cell growth. Mechanistically, KDM5C interacted with BRD4 and stimulated BRD4 enhancer recruitment. Moreover, binding of the BRD4 C-terminus to KDM5C stimulated the H3K4 demethylase activity of KDM5C. The abundance of both KDM5C-associated BRD4 and H3K4me1/3 determined the transcriptional activation of many oncogenes. Notably, depletion or pharmacological degradation of KDM5C dramatically reduced BRD4 chromatin enrichment and significantly increased BETi efficacy across multiple cancer types in both tumor cell lines and patient-derived organoid models. Furthermore, targeting KDM5C in combination with BETi suppressed tumor growth in vivo in a xenograft mouse model. Collectively, this work reveals a KDM5C-mediated mechanism by which BRD4 regulates transcription, providing a rationale for incorporating BETi into combination therapies with KDM5C inhibitors to enhance treatment efficacy.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
·
表观遗传学
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DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Xin Peng,Xin Huang,Shaolu Zhang,Naixin Zhang,Shengfan Huang,Yingying Wang,Zhenxing Zhong,Shan Zhu,Haiwang Gao,Zixiang Yu,Xiaotong Yan,Zhennan Tao,Yuxiang Dai,Zhe Zhang,Xi Chen,Feng Wang,Francois X. Claret,Moshe Elkabets,Ning Ji,Yuxu Zhong,Dexin Kong
PARP inhibitors (PARPi) hold substantial promise in treating glioblastoma (GBM). However, the adverse effects have restricted their broad application. Through unbiased transcriptomic and proteomic sequencing, it is discovered that the BET inhibitor (BETi) Birabresib profoundly alters the processes of DNA replication and cell cycle progression in GBM cells, beyond the previously reported impact of BET inhibition on homologous recombination repair. Through in vitro experiments using established GBM cell lines and patient-derived primary GBM cells, as well as in vivo orthotopic transplantation tumor experiments in zebrafish and nude mice, it is demonstrated that the concurrent administration of PARPi and BETi can synergistically inhibit GBM. Intriguingly, it is observed that DNA damage lingers after discontinuation of PARPi monotherapy, implying that sequential administration of PARPi followed by BETi can maintain antitumor efficacy while reducing toxicity. In GBM cells with elevated baseline replication stress, the sequential regimen exhibits comparable efficacy to concurrent treatment, protecting normal glial cells with lower baseline replication stress from DNA toxicity and subsequent death. This study provides compelling preclinical evidence supporting the development of innovative drug administration strategies focusing on PARPi for GBM therapy.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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转化医学
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产品关联
DOI
PubMed
高影响因子
Cell Reports Medicine
·
2025
·
IF 10.6
Wenhua Wang,Xin Li,Rui Hu,Liang Dong,Shiyao Pei,Liping Jin,Qian Gao,Xiang Chen,Mingzhu Yin
Immunotherapy shows remarkable benefits in treating melanoma, yet existing approaches achieve limited overall responses. Here, we show that a combination of bromodomain and extra-terminal protein family inhibitor, NHWD-870, and Bacillus Calmette-Guérin vaccine is a promising therapeutic strategy for melanomas. Single-cell transcriptome analyses and functional experiments show that the combination therapy significantly inhibited tumor growth by reprogramming T cells toward an immune-activated state, enhancing their cytotoxicity, preventing their exhaustion, and increasing the recruitment of them into the tumor microenvironment. We identify the molecule, MT1, as a direct downstream target of BRD4, which is effectively suppressed by NHWD-870. Furthermore, our findings are reinforced by a humanized patient-derived xenograft (PDX) model, which exhibits notable antitumor effects in humanized tumor-bearing mice treated with the combination therapy. Our study underscores the immense potential of this therapeutic approach for clinical practice, offering promising prospects in overcoming the limitations of current treatments.
研究领域:
肿瘤学
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免疫学
·
分子生物学
·
癌症治疗
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Huijuan Ma,Tingqian Wang,Junfeng Wang,Peiyao Wang,Qi Shu,Ruilin Qin,Sijia Li,Huan Xu
The correlation between formaldehyde (FA) exposure and prevalence of asthma has been widely reported. However, the underlying mechanism is still not fully understood. FA exposure at 2.0 mg/m 3 was found to exacerbate asthma in OVA-induced murine models. IFN-γ, the cytokine produced by T helper 1 (Th1) cells, was significantly induced by FA in serum and bronchoalveolar lavage fluid (BALF) of asthmatic mice, which was different from cytokines secreted by other Th cells. The observation was also confirmed by mRNA levels of Th marker genes in CD4+ T cells isolated from BALF. In addition, increased production of IFN-γ and expression of T-bet in Jurkat T cells primed with phorbol ester and phytohaemagglutinin were also observed with 100 μM FA treatment in vitro . Upregulated STAT1 phosphorylation, T-bet expression and IFN-γ production induced by FA was found to be restrained by STAT1 inhibitor fludarabine, indicating that FA promoted Th1 commitment through the autocrine IFN-γ/STAT1/T-bet pathway in asthma. This work not only revealed that FA could bias Th lineage commitment to exacerbate allergic asthma, but also identified the signaling mechanism of FA-induced Th1 differentiation, which may be utilized as the target for development of interfering strategies against FA-induced immune disorders.
研究领域:
免疫学
·
呼吸病学
·
毒理学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-13
·
IF 14.7
Tang Si,Liu Yaqing,Zhu Jianming,Cheng Xueyu,Liu Lu,Hammerschmidt Katrin,Zhou Jin,Cai Zhonghua
Understanding how organisms have adapted to persist in unpredictable environments is a fundamental goal in biology. Bet hedging, an evolutionary adaptation observed from microbes to humans, facilitates reproduction and population persistence in randomly fluctuating environments. Despite its prevalence, empirical evidence in microalgae, crucial primary producers and carbon sinks, is lacking. Here, we report a bet-hedging strategy in the unicellular microalga Haematococcus pluvialis . We show that isogenic populations reversibly diversify into heterophenotypic mobile and non-mobile cells independently of environmental conditions, likely driven by stochastic gene expression. Mobile cells grow faster but are stress-sensitive, while non-mobile cells prioritise stress resistance over growth. This is due to shifts from growth-promoting activities (cell division, photosynthesis) to resilience-promoting processes (thickened cell wall, cell enlargement, aggregation, accumulation of antioxidant and energy-storing compounds). Our results provide empirical evidence for bet hedging in a microalga, indicating the potential for adaptation to current and future environmental conditions and consequently conservation of ecosystem functions.
研究领域:
生物学
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生态学
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微生物学
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进化生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Long Zheng,Yiwei Zheng,Sijie Wu,Yonglei Zhang,Zhongwen Luo,Yuhan Jiang,Shunxin Guo,Meiting Zou,Lingyi Kong,Xiaobing Wang
The clinical application of CDK4/6 inhibitors is constrained by their narrow indications. To improve therapeutic efficacy against breast cancer, combination therapies using CDK4/6 inhibitors with BET inhibitors are being explored in clinical trials. Our study demonstrates that the CDK4/6 inhibitor Abemaciclib and the BRD4 inhibitor BQ0 exert a synergistic effect in inhibiting the proliferation of triple-negative breast cancer (TNBC) cells in vitro. Based on these findings, we designed and synthesized a series of dual-target inhibitors that simultaneously target CDK6 and BRD4. Among the newly synthesized compounds, 7f and 7f15 exhibited potent inhibitory activity against both CDK6 and BRD4, along with remarkable antiproliferative activity on TNBC cells. In vivo studies using the MDA-MB-231 xenograft mouse model revealed that 7f15 exhibits robust antitumor activity without significant adverse effects. The kinases selectivity experimental suggested that 7f15 is a pan-BET inhibitor. In summary, 7f15, hereby designated as KWZL-7f15, is a novel dual CDK6/BET inhibitor with promising therapeutic potential for the treatment of triple-negative breast cancer.
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2026
·
IF 5.7
Lingling Wei,Haoyu Jin,Zhongke Ji,Haoyang Tian,Jiayang Han,Yanyan Liu,Wanjia Li,Di Liu,Hui Song
Oral squamous cell carcinoma (OSCC) remains a challenging malignancy with high recurrence and metastasis rates, often limited by insufficient immunogenicity and a suppressive tumor microenvironment. Immunogenic cell death (ICD) offers a promising approach to convert cell death into antitumor immunity, yet its efficacy depends on precise modulation of autophagy and endoplasmic reticulum stress (ERS). Here, we report that combining the BET inhibitor JQ1 with the autophagy inhibitor chloroquine (CQ) synergistically amplifies ERS, leading to enhanced ICD in OSCC models. This combination promotes robust damage-associated molecular pattern (DAMP) release, dendritic cell activation, and antigen-specific CD8⁺ T-cell responses. To enable localized and efficient delivery, we engineered self-assembled JQ1/CQ nanoparticles stabilized through π–π stacking and integrated them into dissolvable cryomicroneedles. This minimally invasive platform ensures sustained drug release, improves tumor accumulation, and minimizes systemic exposure. Our study not only elucidates a druggable autophagy–ERS–ICD axis but also provides a versatile transdermal delivery strategy with potential applicability to a range of solid tumors.
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Yin Zhang,Ranran Yu,Cheng Zhao,Jiawei Liang,Yixuan Zhang,Haochen Su,Jing Zhao,Hao Wu,Shijin Xu,Ziying Zhang,Lei Wang,Xiaoping Zou,Yun Zhu,Shu Zhang,Ying Lv
BRD4 is a member of the BET protein family involved in chromatin remodeling and transcriptional regulation. Several BET inhibitors (BETi) have entered clinical trials, demonstrating potential in inducing cancer cell apoptosis and tumor regression. However, resistance to BETi is common in solid tumors. In pancreatic cancer, it is found that cancer-associated fibroblasts (CAFs) in the tumor microenvironment reduce the BET inhibitor JQ1 sensitivity by inducing BRD4 expression. Moreover, CAFs play a crucial role in the formation of a dense stromal barrier. Therefore, targeting CAFs in the tumor microenvironment of pancreatic cancer not only enhances cancer cells sensitivity to JQ1 but also increases drug perfusion and improves oxygen supply, thus reducing glycolysis and limiting energy supply. To address this challenge, a homologous targeting mechanism utilizing activated fibroblast membrane-coated liposomes is proposed for specific drug precise target to CAFs-rich pancreatic cancer. Additionally, TAT peptides enable liposomes penetration, delivering PFD for targeted anti-fibrotic therapy, reducing extracellular matrix generation and glycolysis, and enhancing JQ1 delivery and sensitivity. In conclusion, the findings indicate the tremendous potential of this CAFs-targeting liposomal delivery system in pancreatic cancer.
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHEMICAL AND ENGINEERING DATA
·
2016
·
IF 1.835
Wei Su,Ai Zhang,Yan Sun,Meng Ran,Xiaojing Wang
Adsorption isotherms of pure C2H4 and C3H6 were measured on 11 adsorbents and at pressures up to 0.8 MPa using a volumetric method. The Brunauer–Emmett–Teller (BET) surface area of the adsorbents had a significant effect on adsorption capacities of both C2H4 and C3H6. The metal organic framework MIL-101 had the highest BET surface area and the highest adsorption capacity. For zeolite molecular sieves 5A, the C2H4 adsorption capacity was higher than that of C3H6, which is opposite to the results for most adsorbents. The isosteric heats of C3H6 on AC-1, 5A, MIL-101, ZIF-8, and SG-1 were higher than those of C2H4. The C3H6/C2H4 separation selectivities were calculated using the ideal solution theory, and the activated carbon AC-1 had the highest separation selectivity of 8.8.
研究领域:
化学工程
·
材料科学
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DOI
高影响因子
CELLULOSE
·
2016
·Vol. 23
·期 2
·1325-1334
·
IF 3.195
Chen Mingjie,Zhang Xueqin,Zhang Aiping,Liu Chuanfu,Sun Runcang
Lignocellulosic biomass aerogels with relatively high Brunauer–Emmett–Teller (BET) surface area and pore volume were prepared directly from bagasse solutions in the present study. Bagasse was dissolved in DMSO/LiCl, treated with cyclic freezing-thawing processes, and regenerated with water. The resulted bagasse hydrogels were solvent-exchanged to t-butanol and subjected to freeze-drying to obtain the lignocellulosic aerogels. The structure of the aerogels was studied with FTIR, nitrogen absorption, SEM, and XRD. The results showed that the aerogels had sheet-like skeletons interconnected with one another to form three-dimensional networks. The highest BET surface area and total pore volume of the aerogels were 185 m 2 /g and 0.46 cm 3 /g, respectively. By adjusting the concentration of bagasse solution in DMSO/LiCl, the structure of the aerogels could be controlled to some extent.
研究领域:
材料科学
·
生物质能
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产品关联
DOI
高影响因子
APPLIED SURFACE SCIENCE
·
2018
·
IF 4.439
Sizhao Zhang,Jian Feng,Junzong Feng,Yonggang Jiang,Feng Ding
Although carbon aerogels derived from naturally occurring materials have been developed extensively, a reasonable synthetic approach using cellulose-resource remains unclear. Here, we report a strategy to prepare carbon aerogels originated from cellulose position-selectively oxidized by TEMPO-oxidized process. Contrary to non-TEMPO-oxidized cellulose-derived carbon aerogels (NCCA) with relative loose structure, TEMPO-oxidized cellulose-derived carbon aerogels (TCCA) with tight fibrillar-continuous network are monitored, suggesting the importance of TEMPO-oxidized modification towards creating the architecture of subsequently produced carbon aerogels. TCCA endows a higher BET area despite owning slightly dense bulk density comparing with that of NCCA. The structural texture of TCCA could be maintained in a way in comparison to TEMPO-oxidized cellulose-derived aerogel, due to the integration and aggregation effect by losing the electric double layer repulsion via ionization of the surface carboxyl groups. FTIR and XPS analyses signify the evidence of non-functionalized carbon-skeleton network formation in terms of TCCA. Further, the mechanism concerning the creation of carbon aerogels is also established. These findings not only provide new insights into the production of carbon aerogels but also open up a new opportunity in the field of functional carbon materials.
研究领域:
材料科学
·
化学工程
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）