ACTA PHARMACOLOGICA SINICA
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2026
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IF 10.4
Li Ju-fei,Wang Hao,Kang Ling,Xu Cheng-cheng,Liu Yuan-chun,Li Zi-xuan,Lin Shao-hao,Wang Ming-zhi,Xu Xiao-min,Wang Pei-pei,Yin Wan-chao,Zhou Yu-bo,Zhou Yu,Li Jia
Metabolic hijacking of tryptophan (Trp) via the IL4I1-AHR axis is a pivotal immune evasion mechanism in cancers, yet therapeutic strategies to disrupt this pathway remain unexplored. Here, we report the identification of ZY-MY-111, a selective small-molecule inhibitor of interleukin-4-induced-1 (IL4I1), through an in-house compound library screening and structural optimization. ZY-MY-111 exhibits potency (IC 50 = 1.86 ± 0.13 μM) in blocking IL4I1-mediated oxidative deamination. Mechanistically, ZY-MY-111 acts as a mixed-type inhibitor, competitively occupying the catalytic pocket of IL4I1 and disrupting Trp-AHR signaling in cells. Functionally, ZY-MY-111 promotes T cell proliferation, enhancing immune responses against the tumor cells. In syngeneic tumor models, ZY-MY-111 achieved 49% tumor growth inhibition in CT26 colon carcinoma ( P < 0.001) and 56% tumor growth inhibition in A20 lymphoma ( P < 0.001) by remodeling the immunosuppressive microenvironment: increasing CD8 + /CD4 + T cell ratios, reducing myeloid-derived suppressor cells (MDSCs, 59% decrease), and enhancing effector memory T cell infiltration. Our findings position IL4I1 inhibition as a potential strategy to restore anti-tumor immunity.
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MICROCHEMICAL JOURNAL
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2026
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IF 5.2
Yi Liang,Ke Huang,Jin-Wen Liu,Yumin Wang
Thioflavin T as split G-quadruplex fluorescent dye was researched. • A novel sensing method based on CoOOH nanoflakes and HCR was proposed. • Label-free and sensitive detection of miRNA-21 was successfully realized. To date, various fluorescent probes for G-quadruplex have been reported. However, the development of fluorescent dyes for split G-quadruplex formed on double-stranded DNA structure still remained largely unexplored. Herein, we have demonstrated that thioflavin T (ThT) was able to intercalate into split G-quadruplex sequence and the formed split G-quadruplex-ThT structure exhibited remarkable fluorescence enhancement. By integrating cobalt oxyhydroxide (CoOOH) nanoflakes and hybridization chain reaction (HCR), a sensitive and label-free biosensing strategy for miRNA detection was proposed. In our design, miRNA-21 was chosen as the model target and it was capable of triggering HCR with two split G-quadruplex sequence-contained hairpin probes, resulting in the generation of long chain-like HCR product. Unlike hairpin probes, the HCR product cannot be adsorbed onto CoOOH nanoflakes because of lower affinity. Consequently, in the presence of ThT, numerous split G-quadruplex-ThT structures on HCR product were formed and the target miRNA was converted into amplified and activatable fluorescence signal. Experimental results demonstrated that this novel sensing strategy can be applied for sensitive and selective detection of miRNA. Moreover, the analysis of miRNA in complex biological media was successfully realized, offering a robust, label-free and cost-effective platform for miRNA-related disease diagnosis and biomedical research. A novel fluorescence biosensing strategy based on cobalt oxyhydroxide (CoOOH) nanoflakes and hybridization chain reaction (HCR) was developed for sensitive and label-free detection of miRNA-21. Download: Download high-res image (161KB) Download: Download full-size image
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JOURNAL OF CONTROLLED RELEASE
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2026
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IF 12.4
Xiu Zhao,Kaikai Zhao,Mengfei Yi,Ruohan Yang,Xuyang Cui,Yi Zhang,Feng Li,Junjie Liu
Tumor chemokines that drives abnormal immune cell niches play a crucial role in impairing the chimeric antigen receptor (CAR)-T cell therapy against solid tumors. Here we develop a biomimetic nanoformulation with chemokine “leverage regulation” capabilities, which can establish matching migration signals to creat an immune cell niche that supports CAR-T cell therapy. The system is constructed using celecoxib (CXB)-loaded poly(d, l -lactide- co -glycolide) (PLGA) nanoparticles and subsequently camouflaging them with mesenchymal stem cell membranes with high CXCR4 expression. Leveraging the characteristic of tumors abnormally upregulating the chemokine CXCL12 to recruit CXCR4-positive immunosuppressive cells, the biomimetic nanoformulations can achieve efficient accumulation in the tumor tissue. These nanoformulations remodel the tumor chemokine milieu by upregulating immunogenic chemokines (CXCL9, CXCL10) to selectively recruit CAR-T cells, while simultaneously serving as a nanobait to neutralize CXCL12, thereby reducing the influx of immunosuppressive cells (such as CAR-Tregs and MDSCs) to enhance the killing efficacy of CAR-T cells. This dual modulation of the chemokine network significantly improves the therapeutic efficacy of CAR-T cells against solid tumors. Our approach represents a promising strategy for advancing CAR-T cell therapy toward clinical applications for soild tumors.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Fei Lin,Dehong Zhang,Saisai Liu,Bo Wu,Jinyu Wang,Tingxu Yan,Ying Jia
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by immune dysregulation, epithelial barrier dysfunction, and gut microbiota imbalance. This study examined the therapeutic potential of isoalantolactone (IAL), a bioactive sesquiterpene lactone naturally occurring in Inula helenium L., using a dextran sulfate sodium–induced murine colitis model. Treatment with IAL significantly mitigated weight loss, improved the disease activity index, preserved colon length, and alleviated goblet cell depletion. Mechanistically, IAL enhanced intestinal barrier integrity by upregulating tight-junction proteins zonula occludens-1, occludin, and mucin 2 and suppressing proinflammatory cytokines interleukin (IL)-6, tumor necrosis factor-α, and IL-1β. Moreover, IAL rebalanced CD4 + /CD8 + T cell ratios in the colon, mesenteric lymph nodes, and spleen. Gut microbiota analysis revealed increased diversity, enrichment of beneficial taxa ( Muribaculaceae , Prevotellaceae_UCG-001 ), and a reduced Firmicutes -to- Bacteroidetes ratio. Metabolomic profiling identified 130 differentially abundant metabolites, including increased levels of anti-inflammatory compounds (e.g., hydroferulic acid) and decreased levels of proinflammatory lipids (e.g., linoleoylcarnitine). Correlation analysis demonstrated an association between gut microbiota and faecal metabolites. In addition, faecal microbiota transplantation confirmed that IAL-modulated microbiota ameliorated colitis, with pseudo-germ-free recipients exhibiting improved barrier function and immune homeostasis. These findings highlight the importance of IAL as a novel therapeutic candidate for UC by modulating host–microbiota interactions; however, clinical validation is warranted.
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Nature Communications
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2026
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IF 18.1
Zhao Lei,Gao Zhongqiang,Yuan Ze,Yang Xiaodie,Li Duxin,Ren Qian,Yu Yunli,Pan Jie,Zheng Yiran,Zhang Xinyun
Inducing antigen-specific regulatory T (T reg ) cells is a promising strategy for treating autoimmune diseases (AID). Here, we present dendritic cells-CD4⁺ T cells (DC-CD4) bispecific tolerogenic nanovesicles (NV) co-loaded with an antigenic peptide and rapamycin. We show that these NVs bring DCs and CD4⁺ T cells into close spatial proximity through CTLA4-CD80/86 and anti-CD4 (aCD4)-CD4 interactions, thereby promoting antigen-specific T reg cell generation. In a collagen-induced arthritis mouse model, the bispecific NVs display enhanced lymph node (LN) tropism and increase antigen-specific T reg cells in LNs and spleen, when administered in both therapeutic and prophylactic settings, resulting in robust efficacy against CIA. Furthermore, arthritogenic cell transfer and adoptive transfer of T reg cells into T reg -ablated mice confirm the pivotal role of bispecific NV-induced antigen-specific T reg cells in mediating the anti-inflammatory efficacy. Collectively, our data support DC-CD4 bispecific tolerogenic NVs as a platform to induce antigen-specific T reg cells for precise immune tolerance in AIDs.
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ARCHIVES OF TOXICOLOGY
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2026
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IF 10.9
Zhao Tong,Zhao Yichen,Mao Tingting,Da Weixuan,Qin Lina,Liu Li,Liu Huan,Cheng Bolun,Wen Yan,Zhang Feng,Jia Yumeng
Kashin-Beck disease (KBD) is a multifactorial endemic osteoarthropathy that has been associated with nutritional and environmental factors, including selenium deficiency and T-2 toxin exposure. However, whether combined selenium deficiency and T-2 toxin exposure affects hepatic xenobiotic metabolism has not been systematically investigated. Male C57BL/6 mice were fed a selenium-adequate or selenium-deficient diet for 4 weeks, followed by another 4 weeks with or without daily oral T-2 toxin (0.2 mg/kg). Plasma selenium and glutathione peroxidase (GPx) activity were measured. Hepatic histology, activities of major mouse cytochrome P450 (Cyp450) isoforms, and corresponding mRNA and protein expression were assessed. RNA sequencing was performed using liver samples from four biological replicates per group to identify differentially expressed genes (DEGs) and enriched pathways. Selenium deficiency was confirmed by significantly reduced plasma selenium levels and GPx activity. Histological examination revealed marked hepatic steatosis. Transmission electron microscopy further showed prominent ultrastructural alterations including endoplasmic reticulum dilation. The activities of five hepatic Cyp450 isoforms, Cyp1a2, Cyp2b10, Cyp2c29, Cyp2c50, and Cyp3a11, were significantly increased to 1.64–2.51 times the control levels, consistent with increased mRNA and protein expression. Combined selenium deficiency and T-2 toxin exposure was associated with increased hepatic Cyp450 enzyme activity and expression, identifying the liver as a responsive target of KBD-related exposures. These findings suggest the need to further evaluate hepatic xenobiotic metabolism in populations from KBD-endemic areas.
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Nature Communications
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2025
·Vol. 16
·期 1
·1-14
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IF 15.7
Wang Peng,Zhao Danyang,Zhang Peng,Hui Xiaobin,Zhang Zhiwei,Wang Rutao,Wang Chengxiang,Ge Xiaoli,Liu Xiaojing,Li Yuguang C.,Yin Longwei
The metallic phase MoS 2 (1T-MoS 2 ) supported metal-nanocatalyst is an appealing material system for accelerating the redox kinetics of non-aqueous Li | |O 2 batteries. However, the drawbacks associated with the surface orbital steric effect and the internal electron coupling results in a detrimental effect for the stability of 1T-MoS 2 , especially for the interface charge transfer. This makes it difficult to incorporate guest metal nanoparticles without compromising the 1 T phase support. To circumvent these issues, here we propose a p-block element (In-O) doping strategy to stabilize the 1 T phase MoS 2 by moderating the surface orbital steric effect and strengthening the internal chemical bonding, and thus for the epitaxial Ru nanocatalyst graft on the stabilized 1T-MoS 2 for Li | |O 2 batteries. The experimental and theoretical analyzes indicate that the In-O-MoS 2 @Ru enhances the O 2 dissociation and facilitates the adsorption of LiO 2 intermediates. This effect promotes the growth of weakly crystalline Li 2 O 2 films during oxygen reduction reaction, which can be more easily decomposed during the oxygen evolution reaction, thereby enhancing the bifunctional-catalytic kinetics. When employed at the positive electrode for non-aqueous Li | |O 2 batteries, In-O-MoS 2 @Ru shows an overpotential of 0.37 V and a cycling life of 284 cycles at 200 mA g −1 with a final discharge specific capacity of 1000 mAh g −1 at 25 °C.
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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催化
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ACS Nano
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2025
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IF 16
Yuchen Wang,Yang Liu,Long Wang,Zhong Chen,Qingsong Ye,Kaiyuan Chen,Chenxuan Zhao,Mingkang Yang,Wen Xia,Min Zhang,Jun Qiao,Guangxin Zhou,Jinhui Wu
The immunosuppressive tumor microenvironment formed by many solid tumors, particularly colon cancer, suppresses innate immune molecule expression and consequently limits T cell infiltration. Microtubule inhibitors were originally developed to eliminate tumors by inducing mitotic arrest. However, recent studies have shown that these inhibitors can also disrupt the microtubule dynamics and enhance the efficacy of immunotherapies. These findings highlight the target microtubule as a promising strategy for immune modulation. In this study, we investigated the use of Combretastatin A4 (CA4), a hydrophobic microtubule inhibitor that targets tumor vascular endothelial cells. To improve its solubility and delivery efficiency, CA4 was encapsulated in human serum albumin to form CA4@Alb. This formulation effectively inhibited microtubules in tumor endothelial cells, resulting in the promoted infiltration of erythrocytes into the tumor microenvironment. These erythrocytes were subsequently phagocytosed by intratumoral macrophages, leading to their pro-inflammatory activation. Notably, erythrophagocytic macrophages upregulated innate immune molecules, including chemokine CXCL10 and costimulatory molecule CD86, and enhanced T cell infiltration and activation. As a result, CA4@Alb significantly improved the responsiveness to T cell-based immunotherapies. Overall, our findings indicate that CA4@Alb effectively reprograms the immunosuppressive microenvironment of colon cancer and holds promising translational potential for enhancing immunotherapy efficacy.
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ACS Applied Materials & Interfaces
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2025
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IF 8.2
Xiaodie Zhao,Anyang Yu,Tian Jiang,Qi Fan,Pingping Sun,Qingyu Xu
Tailoring the crystalline structure and facet orientation of T-Nb2O5 anode electrodes is pivotal for optimizing the Li+ transport kinetics. Herein, a crystallization engineering strategy is employed to synthesize urchin-like T-Nb2O5 microspheres composed of single-crystalline whiskers growing along the (001) orientation. These whiskers are characterized by nearly 100% exposed vertical (001) facets that accelerate Li+ diffusion. Furthermore, the remaining N3– expands the interlayer spacing, which optimizes Li+ transport pathways. Benefiting from these synergetic effects, abundant ion entry and exit sites with smooth ion transport channels promote the rapid Li+ diffusion in the T-Nb2O5 microspheres, delivering a high capacity and improving the rate performance (324 mAh g–1 at 0.05 A g–1, 87.5 mAh g–1 at 5 A g–1). This work presents a strategy of crystallization engineering for the preparation of fast-charging electrode materials and provides deep insights on the correspondence among morphology, lattice structure, and electrochemical performance.
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Advanced Healthcare Materials
·
2025
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IF 9.6
Ranran Guo,Ruixun Chen,Zhenhang Rao,Lugui Wang,Jianing Xi,Yu Zhang,Weisheng Guo,Ye Tian
Immune checkpoint blockade therapy has revolutionized clinical oncotherapy by intercepting immunosuppressive pathways in tumor tissues. Nevertheless, the therapeutic efficacy is limited by a multidimensional immunosuppressive tumor microenvironment, which impedes the activity of tumor-infiltrating immune cells and undermines treatment outcomes. In this study, a zwitterionic polymer is designed for the conjugation and traceless release of a checkpoint inhibition antibody (Atezolizumab), while concurrently enabling the restoration of membrane redox homeostasis on T cell membranes within the oxidative tumor microenvironment. Contrast-enhanced fluorescence imaging in the near-infrared II spectral region with a deep learning network is employed to visualize in vivo dynamics of the antibody conjugates. The antibody conjugates demonstrate enhanced and accelerated tumor accumulation, thereby promoting T cell proliferation and augmenting the antitumor efficacy. Mechanistic investigations reveal that the conjugate-mediated regulation of the T cell surface redox state protects against damage induced by extracellular reactive oxygen species, subsequently mitigating ferroptosis of T cells. In murine models, the antibody conjugates effectively suppressed colorectal tumor growth and recurrence, leading to a significant extension of animal survival. This work thus realizes reversing suppressive immune microenvironment from multiple dimensions with a simple checkpoint inhibitor conjugate, promising for clinical translation and next-generation immune checkpoint blockade therapy.
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ACTA PHARMACOLOGICA SINICA
·
2023
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IF 8.2
Zhang Zi-jian,Wu Qi-fang,Ren An-qi,Chen Qian,Shi Jiang-zhou,Li Jia-peng,Liu Xi-yu,Zhang Zhi-jie,Tang Yu-zhe,Zhao Yuan,Yao Ning-ning,Zhang Xiao-yu,Liu Chang-peng,Dong Ge,Zhao Jia-xuan,Xu Mei-jun,Yue Yun-qiang,Hu Jia,Sun Fan,Liu Yu,Ao Qi-lin,Zhou Fu-ling,Wu Hong,Zhang Tong-cun,Zhu Hai-chuan
Abnormalities of FGFR1 have been reported in multiple malignancies, suggesting FGFR1 as a potential target for precision treatment, but drug resistance remains a formidable obstacle. In this study, we explored whether FGFR1 acted a therapeutic target in human T-cell acute lymphoblastic leukemia (T-ALL) and the molecular mechanisms underlying T-ALL cell resistance to FGFR1 inhibitors. We showed that FGFR1 was significantly upregulated in human T-ALL and inversely correlated with the prognosis of patients. Knockdown of FGFR1 suppressed T-ALL growth and progression both in vitro and in vivo. However, the T-ALL cells were resistant to FGFR1 inhibitors AZD4547 and PD-166866 even though FGFR1 signaling was specifically inhibited in the early stage. Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2α pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS , ASS1 , PHGDH and SLC1A5 , maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells. Targeting FGFR1 and mTOR exhibited synergistically anti-leukemic efficacy. These results reveal that FGFR1 is a potential therapeutic target in human T-ALL, and ATF4-mediated amino acid metabolic reprogramming contributes to the FGFR1 inhibitor resistance. Synergistically inhibiting FGFR1 and mTOR can overcome this obstacle in T-ALL 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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细胞信号传导
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MOLECULAR IMMUNOLOGY
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2026
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IF 3.7
Zeyu Tao,Jingwei Gao,Hongbo Huang,Tao Xu,Tianqi Zhang,Jingtang Liang,Longkai Bao,Shaoping Liao,Long Mo,Jinyi Chi,Limin Li,Li Xie
Human Immunodeficiency Virus (HIV) infection is characterized by the depletion of human CD4 + T cells, in which ferroptosis has been identified as a contributing mechanism. Dysregulation of the canonical Wnt/β-catenin signaling pathway is strongly associated with HIV infection. Our findings demonstrate that Wnt7a activates this pathway. Subsequently, β-catenin translocates to the nucleus, where it interacts with the transcription factor 4 (TCF4) to regulate ferroptosis in T lymphocytes from HIV-infected individuals. Analysis of peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals revealed significantly decreased expression levels of Wnt7a, along with key Wnt/β-catenin pathway components (β-catenin, TCF4) and the ferroptosis regulator GPX4, compared to healthy controls. Concurrently, PBMCs from HIV-infected individuals exhibited elevated levels of ferroptosis. We established an in vitro HIV-infected T lymphocyte model by expanding patient-derived PBMCs using a CD3/CD28/CD2 T cell activator and IL-2. Lentiviral transduction was used to stably overexpress Wnt7a in this model. Wnt7a overexpression successfully activated the Wnt/β-catenin pathway and significantly reduced ferroptosis levels. Furthermore, pharmacological manipulation of ferroptosis modulated Wnt7a expression: treatment with the ferroptosis inhibitor Liproxstatin-1 and Ferrostatin-1 increased Wnt7a expression, while exposure to the ferroptosis inducer RSL-3 decreased it. Flow cytometry analysis confirmed that overexpressing Wnt7a significantly increased the number of CD4 + T cells compared to the control. In summary, Wnt7a activates the Wnt/β-catenin signaling pathway to reduce ferroptosis in T lymphocytes from HIV-infected individuals, likely by targeting GPX4, suggesting a potential new strategy for treating HIV infection by restoring the T lymphocyte population.
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