JOURNAL OF MEDICINAL CHEMISTRY
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2023
·
IF 7.3
Xing-Jie Dai,Li-Juan Zhao,Long-Hua Yang,Ting Guo,Lei-Peng Xue,Hong-Mei Ren,Zhi-Li Yin,Xiao-Peng Xiong,Ying Zhou,Shi-Kun Ji,Hui-Min Liu,Hong-Min Liu,Ying Liu,Yi-Chao Zheng
Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for cancer treatment. Although several LSD1 inhibitors have entered clinical trials, the discovery of novel potent LSD1 inhibitors remains a challenge. In this study, the antipsychotic drug chlorpromazine was characterized as an LSD1 inhibitor (IC50 = 5.135 μM), and a series of chlorpromazine derivatives were synthesized. Among them, compound 3s (IC50 = 0.247 μM) was the most potent one. More importantly, compound 3s inhibited LSD1 in the cellular level and downregulated the expression of programmed cell death-ligand 1 (PD-L1) in BGC-823 and MFC cells to enhance T-cell killing response. An in vivo study confirmed that compound 3s can inhibit MFC cell proliferation without significant toxicity in immunocompetent mice. Taken together, our findings indicated that the novel LSD1 inhibitor 3s tethering a phenothiazine scaffold may serve as a lead compound for further development to activate T-cell immunity in gastric cancer.
研究领域:
肿瘤学
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免疫学
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药理学
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DOI
PubMed
高影响因子
Frontiers in Immunology
·
2023
·
IF 7.3
Ben Yi,Shuai Zhang,Suying Yan,Yanfei Liu,Zhiqiang Feng,Tianhao Chu,Jun Liu,Wei Wang,Jun Xue,Chunze Zhang,Yijia Wang
Introduction Tumor-infiltrating T lymphocytes in the tumor microenvironment are critical factors influencing the prognosis and chemotherapy outcomes. As a Chinese herbal medicine, Marsdenia tenacissima extract (MTE) has been widely used to treat cancer in China. Its immunoregulatory effects on tumor-associated macrophages is well known, but whether it regulates tumor-infiltrating T-cell functions remains unclear. Method We collected 17 tumor samples from MTE-administered colorectal cancer patients, 13 of which showed upregulation of CD3+/CD8+ tumor-infiltrating T cells. Further in vitro and in vivo experiments were performed to investigate the regulatory effects of MTE on tumor-infiltrating T cells and immune escape of tumors. Results Under single and co-culture conditions, MTE inhibited TGF-β1 and PD-L1 expression in the colorectal cancer (CRC) cell lines HCT116 and LoVo. In Jurkat cells, MTE inhibited FOXP3 and IL-10 expression, increased IL-2 expression, but had no effect on PD-1 expression. These findings were confirmed in vitro using subcutaneous and colitis-associated CRC mouse models. MTE also increased the density of CD3+/CD8+ tumor-infiltrating T cells and exhibited considerable tumor-suppressive effects in these two tumor mouse models. Conclusions Our findings suggested that MTE inhibits the immune escape of cancer cells, a precipitating factor increasing the immune response of T lymphocytes.
研究领域:
肿瘤学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-16
·
IF 14.7
Ye Qian-Ni,Zhu Long,Liang Jie,Zhao Dong-Kun,Tian Tai-Yu,Fan Ya-Nan,Ye Si-Yi,Liu Hua,Huang Xiao-Yi,Cao Zhi-Ting,Shen Song,Wang Jun
The functions of natural killer (NK) and T cells in innate and adaptive immunity, as well as their functions in tumor eradication, are complementary and intertwined. Here we show that utilization of multi-specific antibodies or nano-antibodies capable of simultaneously targeting both NK and T cells could be a valuable approach in cancer immunotherapy. Here, we introduce a tri-specific Nano-Antibody (Tri-NAb), generated by immobilizing three types of monoclonal antibodies (mAbs), using an optimized albumin/polyester composite nanoparticle conjugated with anti-Fc antibody. This Tri-NAb, targeting PDL1, 4-1BB, and NKG2A (or TIGIT) simultaneously, effectively binds to NK and CD8 + T cells, triggering their activation and proliferation, while facilitating their interaction with tumor cells, thereby inducing efficient tumor killing. Importantly, the antitumor efficacy of Tri-NAb is validated in multiple models, including patient-derived tumor organoids and humanized mice, highlighting the translational potential of NK and T cell co-targeting.
研究领域:
免疫学
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肿瘤学
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生物技术
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2022
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IF 7.129
Wenyu Miao,Lingling He,Yong Zhang,Xiaoyu Zhu,Yangming Jiang,Pengpeng Liu,Tao Zhang,Chunqi Li
Glucocorticoids (GCs) have been widely detected in the aquatic system. However, the hazardous effects of GCs on aquatic organisms were underestimated, and the mechanisms of GCs-induced toxic effects in fish were largely unknown. The zebrafish larvae at 3 dpf were exposed to dexamethasone (DEX) for 48 h, and the toxic effects and the underlying mechanisms were investigated in the current study. The T cells were ablated in zebrafish larvae after being treated with 1, 3, 10, 30 and 100 μM of DEX for 48 h. In addition, osteoporosis was induced and the regeneration of the caudal fin was inhibited, by 48 h-exposure to 10, 30 and 100 μM of DEX. The transcriptomic analysis, biochemical parameters and gene expression profiles revealed that ferroptosis possibly contributed to the DEX-induced toxic effects in zebrafish larvae. Finally, Fer-1 treatment partially attenuated the DEX-induced T cell ablation, but not osteoporosis in zebrafish larvae. Taken together, the current study proved the toxic effects of DEX on zebrafish larvae, and elucidated that ferroptosis was involved in DEX-induced toxicity, providing strong evidence for the toxic effects of GCs on aquatic organisms.
研究领域:
水生毒理学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
RSC Advances
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2017
·Vol. 7
·期 82
·52327-52336
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IF 3.108
Lei Guo,Zhen Yang,Shaotao Zhi,Zhu Feng,Chong Lei,Yong Zhou
In this study, we describe an innovative micro-fluxgate immunosensor based on superparamagnetic Dynabeads for the detection of cardiac troponin T (cTnT), an important biomarker for cardiovascular diseases. The fluxgate sensor developed in this study uses a double layer of Co-based amorphous ribbons as a sensing element and three-dimensional solenoid copper coils to control the sensitive core. The system was fabricated through a standard micro-fabrication process, including thick photoresist lithography and electroplating. Superparamagnetic Dynabeads were employed as recognition tags and double polyclonal antibody pairs combined using streptavidin–biotin binding were employed to specifically capture and label the cTnT coupled with magnetic beads on a separate Au film-coated wafer via a classical sandwich immunoassay process. Series optimization of the assay parameters was performed to achieve optimal detection parameters. Under optimal conditions, the detection and quantification of cTnT was performed by sensing the magnetic signal of the cTnT-labeled Dynabeads with the micro-fluxgate sensor. The resulting biosystem successfully detected cTnT with satisfactory sensitivity, reproducibility, stability, and specificity. A minimum detectable limit of 0.01 ng mL−1 was achieved with a linearity range of 0.01–10 ng mL−1, demonstrating the high sensitivity of this novel system. In addition to the superior detection performance, the proposed sensor is convenient to manipulate, entirely lab-free, provides a quick result, and is portable. These factors suggest that this system has the potential to be applied as a point-of-care diagnostic tool for cardiovascular disease.
研究领域:
医学诊断
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生物传感器
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纳米技术
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产品关联
DOI
高影响因子
Cell Metabolism
·
2023
·
IF 29
Jie Cheng,Jinxin Yan,Ying Liu,Jiangzhou Shi,Haoyu Wang,Hanyang Zhou,Yinglin Zhou,Tongcun Zhang,Lina Zhao,Xianbin Meng,Haipeng Gong,Xinxiang Zhang,Haichuan Zhu,Peng Jiang
Metabolic alterations in the microenvironment significantly modulate tumor immunosensitivity, but the underlying mechanisms remain obscure. Here, we report that tumors depleted of fumarate hydratase (FH) exhibit inhibition of functional CD8 + T cell activation, expansion, and efficacy, with enhanced malignant proliferative capacity. Mechanistically, FH depletion in tumor cells accumulates fumarate in the tumor interstitial fluid, and increased fumarate can directly succinate ZAP70 at C96 and C102 and abrogate its activity in infiltrating CD8 + T cells, resulting in suppressed CD8 + T cell activation and anti-tumor immune responses in vitro and in vivo. Additionally, fumarate depletion by increasing FH expression strongly enhances the anti-tumor efficacy of anti-CD19 CAR T cells. Thus, these findings demonstrate a role for fumarate in controlling TCR signaling and suggest that fumarate accumulation in the tumor microenvironment (TME) is a metabolic barrier to CD8 + T cell anti-tumor function. And potentially, fumarate depletion could be an important strategy for tumor immunotherapy.
研究领域:
肿瘤学
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免疫学
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代谢学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ALLOYS AND COMPOUNDS
·
2025
·
IF 6.3
Zhengyan Hao,Zhiwei Zhang,Xijia Yang,Xuesong Li,Yang Gao,Liying Wang,Yuxin Huang,Wei Lü
Zinc-ion hybrid supercapacitors (ZIHSCs) have garnered widespread attention due to their integration of the excellent characteristics of both batteries and capacitors. This study employs a synergistic strategy combining hydrothermal and high-temperature calcination methods to construct a nanosphere-structured T-Nb 2 O 5 composite anode material coated with reduced graphene oxide (rGO) on a flexible carbon cloth (CC) substrate (T-Nb 2 O 5 /rGO@CC), in conjunction with a hierarchical super-mesoporous activated carbon cathode (ACcp@CC) derived from discarded citrus peel. The rGO coating structure suppresses the volume expansion of the internal nanostructure caused by charging and discharging, effectively enhancing mechanical stability. At the same time, the three-dimensional conductive network of rGO effectively compensates for the poor intrinsic conductivity of Nb 2 O 5 . The constructed ZIHSC delivers a capacitance of 718.56 mF cm −2 at 1 mA cm −2 , and achieves a maximum energy density of 399.20 μWh cm −2 at 1 mW cm −2 . Furthermore, after 50,000 ultralong-cycle, the capacity retention rate is 104.17 %. The assembled flexible device not only possesses excellent mechanical properties but also delivers a specific capacitance of 389.89 mF cm −2 at 1 mA cm −2 , providing long-term power for various electronic devices. This study provides a solid theoretical reference for the design of stable composite structures and the investigation of ultra-long cycling performance in niobium-based electrode materials.
研究领域:
材料科学
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电化学
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储能技术
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纳米技术
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复合材料
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产品关联
DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Tingting Wu,Lulu Wang,Chen Jian,Chen Gao,Yajing Liu,Zhiwen Fu,Chen Shi
Refractory fracture presents an intractable challenge in trauma treatment. Selective polarization of macrophages as well as the recruitment of osteogenic precursor cells play key roles in osteogenic differentiation during fracture healing. Here we constructed regulatory T cell (Treg)-derived exosomes (Treg-Exo) for the treatment of fracture. The obtained exosomes displayed a spheroid shape with a hydrated particle size of approximately 130 nm. With further purification using CD39 and CD73 antibody-modified microfluidic chips, CD39 and CD73 specifically expressing exosomes were obtained. This kind of Treg-Exo utilized the ectonucleotidases of CD39 and CD73 to catalyze the high level of ATP in the fracture area into adenosine. The generated adenosine further promoted the selective polarization of macrophages. When interacting with mesenchymal stem cells (MSCs, osteogenic precursor cells), both Treg-Exo and Treg-Exo primed macrophages facilitated the proliferation and differentiation of MSCs. After administration in vivo , Treg-Exo effectively promoted fracture healing compared with conventional T cell-derived exosome. To further improve the delivery efficacy of exosomes and integrate multiple biological processes of fracture healing, an injectable hydrogel was fabricated to co-deliver Treg-Exo and stromal cell-derived factor 1 alpha (SDF-1α). With the dual effect of Treg-Exo for macrophage polarization and SDF-1α for MSC recruitment, the multifunctional hydrogel exerted a synergistic effect on fracture repair acceleration. This study provided a promising therapeutic candidate and synergistic strategy for the clinical treatment of fracture.
研究领域:
免疫学
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再生医学
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骨科
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细胞生物学
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DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2024
·Vol. 9
·期 1
·1-18
·
IF 40.8
Yang Chuan,Wang Xueping,To Kenneth K. W.,Cui Caimei,Luo Min,Wu Shaocong,Huang Lamei,Fu Kai,Pan Can,Liu Zeyu,Fan Teng,Yang Caibo,Wang Fang,Fu Liwu
Circulating tumor cells (CTCs) are precursors of distant metastasis in a subset of cancer patients. A better understanding of CTCs heterogeneity and how these CTCs survive during hematogenous dissemination could lay the foundation for therapeutic prevention of cancer metastasis. It remains elusive how CTCs evade immune surveillance and elimination by immune cells. In this study, we unequivocally identified a subpopulation of CTCs shielded with extracellular vesicle (EVs)-derived CD45 (termed as CD45 + CTCs) that resisted T cell attack. A higher percentage of CD45 + CTCs was found to be closely correlated with higher incidence of metastasis and worse prognosis in cancer patients. Moreover, CD45 + tumor cells orchestrated an immunosuppressive milieu and CD45 + CTCs exhibited remarkably stronger metastatic potential than CD45 − CTCs in vivo. Mechanistically, CD45 expressing on tumor surfaces was shown to form intercellular CD45-CD45 homophilic interactions with CD45 on T cells, thereby preventing CD45 exclusion from TCR-pMHC synapse and leading to diminished TCR signaling transduction and suppressed immune response. Together, these results pointed to an underappreciated capability of EVs-derived CD45-dressed CTCs in immune evasion and metastasis, providing a rationale for targeting EVs-derived CD45 internalization by CTCs to prevent cancer metastasis.
研究领域:
肿瘤学
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免疫学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Sustainable Food Systems
·
2025
·
IF 3.1
Chang Ma,Hooi Tin Ong,Hoon Koon Teoh,Yue Ling Wang,Zhong Han Zhu,Yan Liu,Juan Du
Background: T-2 toxin is a highly toxic mycotoxin that poses serious risks to food safety and human health. There is an urgent need for sensitive, selective, and reliable analytical methods for its detection in complex food matrices.Methods: We developed a novel ratiometric fluorescence immunoassay based on gold nanoparticles encapsulated in manganese dioxide nanosheets (AuNP@MnO₂), which exhibit intrinsic oxidase-like activity. The assay utilizes dual-emission fluorescence (at 430 nm and 570 nm) and quantifies T-2 toxin by measuring the fluorescence intensity ratio (F₄₃₀/F₅₇₀), thereby minimizing environmental and instrumental variability.Results: The method demonstrated excellent linearity over a wide concentration range (0.082–60.00 ng/mL) with a low detection limit of 0.068 ng/mL. High specificity was achieved, showing negligible cross-reactivity against common mycotoxins such as aflatoxin B₁, zearalenone, fumonisin B₁, ochratoxin A, and deoxynivalenol. In spiked corn samples, recoveries ranged from 76.94% to 99.48%, confirming good accuracy, stability, and reproducibility.Conclusion: This ratiometric immunoassay significantly enhances detection precision by self-calibrating through an internal fluorescence reference. Its simplicity, sensitivity, and robustness in real food samples make it a promising tool for rapid and reliable monitoring of T-2 toxin in food safety applications.
✓ 已验证
DOI
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
·
2024
·
IF 4.9
Wenwen Li,Jihui Li,Jian Han,Kaili Liu,Huixin Zhang,Jianxin Chen
With the accelerated development of industry, which generates large quantities of sewage discharged into the aquatic environment, serious impacts on both environmental and human health. Detecting various organic contaminants in water sources has become common, presenting huge challenges for water treatment. Metal-organic frameworks are characterized by their rich porous structures and high chemical activity, making them ideal adsorbents for removing organic pollutants from water. In this study, sodium dodecylbenzene sulfonate is added to the precursor solution of MIL-101(Cr)-Cl 2 and synthesized hierarchical porous structure adsorbents MIL-SDBS-X, using hydrothermal synthesis to enhance their adsorption capacity, making efficient and rapid removal of bisphenol A(BPA) and chromium black T(EBT), two common organic pollutants in water, which MIL-SDBS-0.7 was the most effective. MIL-SDBS-0.7 exhibites great potential in the adsorption of BPA and EBT for its high adsorption capacity (260.5 mg -1 ·g -1 and 272.3 mg -1 ·g -1 ) and rapid adsorption (equilibrium could be achieved in 15 minutes), The findings reveal adsorption kinetics aligns with the pseudo-second-order model and the Langmuir equation best fits to study adsorption of MIL-SDBS-0.7 to BPA and EBT. Thermodynamic parameters affirm the exothermic and higher spontaneity behavior of the adsorption process . Moreover, the adsorption mechanism of MIL-SDBS-0.7 was explored, illustrating the crucial roles of effects of hydrogen bonding π-π stacking and pore filling in the adsorption of BPA and EBT. Therefore, this work not only provided a convenient strategy for the preparation of efficient and fast MIL-SDBS-0.7 hierarchical porous material but also highlighted the promising potential of synthesized absorbents as an effective adsorbent for organic pollutants in wastewater treatment and environmental remediation.
研究领域:
环境科学
·
材料科学
✓ 已验证
产品关联
DOI
高影响因子
CELL
·
2024
·
IF 45.5
Jinjia Zhang,Junhong Li,Yongqiang Hou,Yao Lin,Hao Zhao,Yiran Shi,Kaiyun Chen,Cheng Nian,Jiayu Tang,Lei Pan,Yunzhi Xing,Huan Gao,Bingying Yang,Zengfang Song,Yao Cheng,Yue Liu,Min Sun,Yueyue Linghu,Jiaxin Li,Haitao Huang,Zhangjian Lai,Zhien Zhou,Zifeng Li,Xiufeng Sun,Qinghua Chen,Dongxue Su,Wengang Li,Zhihai Peng,Pingguo Liu,Wei Chen,Hongling Huang,Yixin Chen,Bailong Xiao,Lilin Ye,Lanfen Chen,Dawang Zhou
Alterations in extracellular matrix (ECM) architecture and stiffness represent hallmarks of cancer. Whether the biomechanical property of ECM impacts the functionality of tumor-reactive CD8 + T cells remains largely unknown. Here, we reveal that the transcription factor (TF) Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion of tumor-reactive CD8 + T cells. Osr2 expression is selectively induced in the terminally exhausted tumor-specific CD8 + T cell subset by coupled T cell receptor (TCR) signaling and biomechanical stress mediated by the Piezo1/calcium/CREB axis. Consistently, depletion of Osr2 alleviates the exhaustion of tumor-specific CD8 + T cells or CAR-T cells, whereas forced Osr2 expression aggravates their exhaustion in solid tumor models. Mechanistically, Osr2 recruits HDAC3 to rewire the epigenetic program for suppressing cytotoxic gene expression and promoting CD8 + T cell exhaustion. Thus, our results unravel Osr2 functions as a biomechanical checkpoint to exacerbate CD8 + T cell exhaustion and could be targeted to potentiate cancer immunotherapy.
研究领域:
免疫学
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癌症生物学
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细胞生物学
·
转录调控
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）