BIOMEDICINE & PHARMACOTHERAPY
·
2025
·
IF 7.5
Yunqiu Chen,Jiayun Ying,Zhiyao Li,Zhen Ning Tony He,Jiani Zhan,Heng Liang,Yuying Liu,Yijia Chen,Xuewen Li,Ting Zhu,Chunxiang Kuang,Guoping Lu,Qing Yang
Indoleamine-2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in tryptophan (Trp) catabolism along kynurenine (Kyn) pathway. Increased IDO1 activity has been noticed in patients with sepsis, while IDO1’s involvement in sepsis, especially in the initial cytokine storm phase is not yet completely understood. Using the GEO database and clinical samples of sepsis, current study revealed that IDO1-AHR-CYP1A1 axis was significantly upregulated and closely related to cytokine storm in septic patients. With cell models of cytokine storm, it was found that IDO1 promoted cytokine storm and the apoptosis of model cells via AHR-CYP1A1, and IDO1-AHR-CYP1A1 axis correlated classic cytokine storm signal pathway including STAT3, NF-κB/STAT1, JNK/p38. With mouse models of septic cytokine storm, it was shown that IDO1 inhibitors could block the upregulated IDO1-AHR-CYP1A1 axis, reduce the enhanced inflammatory cytokine levels, decrease the phosphorylation of classic cytokine storm signal pathway, rescue organ damage, and increase survival rate. It was also found that IDO1 activation occurred after the increase of inflammatory cytokine levels. Therefore, classic cytokine storm signal pathways, inflammatory cytokines and IDO1-AHR-CYP1A1 axis form a tripartite interaction loop to promote cytokine storm. IDO1 inhibitors were able to block this process.
研究领域:
免疫学
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医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Jiani Zhan,Yijia Chen,Yuying Liu,Yunqiu Chen,Zhiyao Li,Xuewen Li,Zhenning He,Fangzhou Meng,Xiaoyang Qian,Lili Yang,Qing Yang
Ferroptosis is a type of cell death marked by iron-dependent lipid peroxide accumulation. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the catabolism of tryptophan through kynurenine pathway, participates in the development of multiple tumor types. However, the role of IDO1 in tumor ferroptosis is unclear. In this study, we identified IDO1 as a key regulator of ferroptosis in lung cancer. With Erastin-treated lung cancer cells, we found that IDO1 inhibited ferroptosis, reduced the generation of lipid peroxide and ROS. Mechanistically, IDO1 promoted the expression of nuclear factor erythroid 2-related factor 2 (NRF2) through activating aryl hydrocarbon receptor (AhR) pathway. IDO1 up-regulated the expression of solute carrier family 7 member 11 (SLC7A11) and the activity of pentose phosphate pathway (PPP) via AhR-NRF2 axis, promoted the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby inhibiting ferroptosis. Moreover, combined treatment with IDO1 inhibitor and Erastin inhibited tumor growth, down-regulated SLC7A11 expression and PPP activity, promoted tumor ferroptosis in lung cancer-bearing mice. In conclusion, this study revealed the function of IDO1 in lung cancer ferroptosis and provided a new strategy for lung cancer therapy.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Hou Xi-xi,Gong Xiao-qing,Mao Long-fei,Sun Ge,Yang Jian-xue
Erlotinib is a highly specific and reversible epidermal growth factor receptor tyrosine kinase inhibitor for the targeted therapy of non-small-cell lung cancer (NSCLC) However, the efficacy of erlotinib is limited because the development of drug resistance during chemotherapy. Indoleamine 2,3-dioxygenase-1 (IDO1) is a rate-limiting tryptophan catabolic enzyme that is activated in many human cancers. In this study, we designed a series of erlotinib-based 1,2,3-triazole compounds by combining erlotinib with phenyl or benzyl azide. Attentive FP prediction model was used to predict the bioactivity of those compounds. We discovered that most of the erlotinib-based 1,2,3-triazole compounds are capable of suppressing IDO1 activities in vitro experiments. Among them, compound 14b (IC50 = 0.59 ± 0.05 μM) had the strongest inhibitory effect on IDO1. In addition, compound 14b significantly inhibited tumor growth comparable to the antitumor activity of erlotinib and the IDO1 inhibitor epacadostat in murine tumor models.
研究领域:
药理学
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肿瘤学
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生物化学
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DOI
PubMed
高影响因子
Oncologie
·
2024
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IF 1.4
Chenchen Jin,Xuejiao Xu,Tao Li,Chunxue Zhang,Jianqing Peng,Chao Liu,Weifeng Zheng,Xu Zhang
Objectives
Colorectal cancer (CRC) is a global challenge, and heat shock protein 90 (HSP90) is identified as a key driver in cancer progression. However, the tumor-promoting mechanism of HSP90 in CRC, particularly HSP90AB1, remains unclear. This study aims to explore and analyze the oncogenic mechanism of HSP90AB1 in CRC and identify potential therapeutic targets.
Materials and methods
HSP90AB1 expression underwent analysis in CRC cell lines and tissues at mRNA and protein levels. Through the use of shRNA, targeted suppression of HSP90AB1 was achieved in CRC cell lines, enabling analysis of its influence on cell proliferation, invasion, apoptosis, and cell cycle progression. Subsequent investigation focused on elucidating the regulatory relationship between HSP90AB1 and IDO1, employing a combination of bioinformatics approaches and in vitro /vivo experiments. These efforts confirmed IDO1 as a downstream target of HSP90AB1 and provided insight into its role in driving CRC progression.
Results
HSP90AB1 exhibits overexpression in both CRC cell lines and tumor tissues (p<0.05). Its downregulation impedes cell proliferation and invasion (p<0.01), promotes apoptosis and cell cycle arrest (p<0.05). Investigation reveals that decreased HSP90AB1 leads to the inhibition of IDO1 (p<0.01), suggesting that IDO1 regulation plays a crucial role in mediating the pro-tumorigenic effects of HSP90AB1. In vivo experiments confirm the substantial reduction in tumor growth upon HSP90AB1 knockdown in xenograft models (p<0.01). However, this tumor-suppressive effect is reversed upon IDO1 overexpression (p<0.01), highlighting IDO1 as a downstream target of HSP90AB1 in CRC progression.
Conclusions
HSP90AB1 exerts a regulatory role in the progression of CRC by upregulating IDO1.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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产品关联
DOI
高影响因子
Future Medicinal Chemistry
·
2021
·Vol. 13
·期 13
·
IF 3.808
Xin Lu,Yijun Liu,Nan Qin,Hongyu Yang,Yuting Qiao,Xueyang Jiang,Yao Chen,Feng Feng,Wenyuan Liu,You Zhou,Haopeng Sun
Background: Alzheimer's disease is a multifactorial neurological disorder seen in elderly people. Loss of cholinergic transmission and unbalanced tryptophan metabolism kynurenine pathway have been demonstrated in neuropsychiatric diseases. Methods & results: Among the two series of synthesized compounds, compounds 5c and 5h were identified as effective dual BChE/IDO1 inhibitors, with well-balanced micromolar activity. Compounds 5c and 5h exhibited promising ability to ameliorate behavioral impairment by Morris water maze. The safety of miconazole analogs was also validated by PC12 and SH-SY5Y cell lines. Conclusion: These results highlight the ability of 5c and 5h to treat Alzheimer's disease.
研究领域:
神经科学
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药物化学
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老年医学
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DOI
PubMed
高影响因子
Pharmaceutics
·
2024
·Vol. 16
·期 7
·870
·
IF 4.9
Zikang Xing,Xuewen Li,Zhen Ning Tony He,Xin Fang,Heng Liang,Chunxiang Kuang,Aiying Li,Qing Yang
Glioma is characterized by strong immunosuppression and excessive angiogenesis. Based on existing reports, it can be speculated that the resistance to anti-angiogenic drug vascular endothelial growth factor A (VEGFA) antibody correlates to the induction of novel immune checkpoint indoleamine 2,3-dioxygenase 1 (IDO1), while IDO1 has also been suggested to be related to tumor angiogenesis. Herein, we aim to clarify the potential role of IDO1 in glioma angiogenesis and the mechanism behind it. Bioinformatic analyses showed that the expressions of IDO1 and angiogenesis markers VEGFA and CD34 were positively correlated and increased with pathological grade in glioma. IDO1-overexpression-derived-tryptophan depletion activated the general control nonderepressible 2 (GCN2) pathway and upregulated VEGFA in glioma cells. The tube formation ability of angiogenesis model cells could be inhibited by IDO1 inhibitors and influenced by the activity and expression of IDO1 in condition medium. A significant increase in serum VEGFA concentration and tumor CD34 expression was observed in IDO1-overexpressing GL261 subcutaneous glioma-bearing mice. IDO1 inhibitor RY103 showed positive anti-tumor efficacy, including the anti-angiogenesis effect and upregulation of natural killer cells in GL261 glioma-bearing mice. As expected, the combination of RY103 and anti-angiogenesis agent sunitinib was proved to be a better therapeutic strategy than either monotherapy.
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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神经科学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
·
IF 5.988
Xu Gui-Qing,Gong Xiao-Qing,Zhu Ying-Ying,Yao Xiao-Jun,Peng Li-Zeng,Sun Ge,Yang Jian-Xue,Mao Long-Fei
Indoleamine 2,3-dioxygenase 1 (IDO1) plays a predominant role in cancer immunotherapy which catalyzes the initial and rate limiting steps of the kynurenine pathway as a key enzyme. To explore novel IDO1 inhibitors, five derivatives of erlotinib-linked 1,2,3-triazole compounds were designed by using a structure-based drug design strategy. Drug-target interactions (DTI) were predicted by DeePurpose, an easy-to-use deep learning library that contains more than 50 algorithms. The DTI prediction results suggested that the designed molecules have potential inhibitory activities for IDO1. Chemical syntheses and bioassays showed that the compounds exhibited remarkable inhibitory activities against IDO1, among them, compound e was the most potent with an IC50 value of 0.32 ± 0.07 μM in the Hela cell assay. The docking model and ADME analysis exhibited that the effective interactions of these compounds with heme iron and better drug-likeness ensured the IDO1 inhibitory activities. The studies suggested that compound e was a novel and interesting IDO1 inhibitor for further development.
研究领域:
癌症研究
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药物化学
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药物设计
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生物信息学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Mengna Wang,Yuhong Liu,Yanshi Li,Tao Lu,Min Wang,Zhaobo Cheng,Lin Chen,Tongling Wen,Min Pan,Guohua Hu
The clinical efficacy of immune checkpoint blockade (ICB) therapy is significantly compromised in the metabolically disordered tumor microenvironment (TME), posing a formidable challenge that cannot be ignored in current antitumor strategies. In this study, TME-responsive nanoparticles (HMP1G NPs) loaded with 1-methyltryptophan (1-MT; an indoleamine 2,3-dioxygenase 1 [IDO1] inhibitor,) and S-nitrosoglutathione (GSNO; a nitric oxide donor) is developed to enhance the therapeutic efficacy of 1-MT-mediated ICB. The HMP1G NPs responded to H + and glutathione in the TME, releasing Mn 2+ , GSNO, and 1-MT. The released Mn 2+ catalyzed the production of abundant reactive oxygen species and nitric oxide from hydrogen peroxide and GSNO, and the generated nitric oxide, synergistically with 1-MT, inhibited the accumulation of kynurenine mediated by IDO1 in the tumor. Mechanistically, HMP1G NPs downregulated tumor cell-derived IDO1 via the aryl hydrocarbon receptor/signal transducer and activator of transcription 3/interleukin signaling axis to improve kynurenine/tryptophan metabolism and immunosuppression. In a murine breast cancer model, treatment with HMP1G NPs elicited effective antitumor immunity and enhanced survival outcomes. This study highlights a novel nano-platform that simultaneously improves metabolism and enhances ICB efficacy to achieve a new and efficient antitumor strategy.
研究领域:
肿瘤学
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免疫疗法
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纳米技术
·
癌症生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 13.2
Yanming Xia,Lixin Hu,Xiaohu Wang,Mingxi Li,Bo Shi,Siqi Zhu,Yutong Wu,Shuting Xiang,Lifang Yin,Suxin Li
Stimulator of interferon genes (STING) is a promising therapeutic target against cancer by bridging the innate and adaptive immunity. However, STING-based monotherapy shows compromised efficacy and dose-limited toxicity in early-stage clinical trials. Here we reveal that indoleamine 2, 3-dioxygenase 1 (IDO1) serves as an inherent negative regulator of STING signaling in dendritic cells to restrain antitumor immune responses. Besides as a consequence of STING signaling that contributes to immune suppression, IDO1 concurrently suppresses STING activity via its metabolites, thus establishing a negative feedback loop. Building on this insight, we develop a two-in-one nanosystem (SIANP) perturbing this inhibitory machinery to amplify STING-mediated antitumor activity. SIANP accumulates at tumor tissues, displays tropism toward dendritic cells in vivo , and facilitates cytosolic co-delivery of STING agonist and IDO1 siRNA at single-cell level, leading to elevated antigen presentation and CD8 + T cell priming with reduced T cell exhaustion or toxicity. This coordination suppresses tumor growth and prolongs survival in multiple established, metastatic, and recurrent tumor models. Remarkably, blockade of IDO1 by SIANP significantly amplifies STING signaling in resected human patient tissues. This work presents a robust nanoengineering approach to overcome immune tolerance arising from negative feedback loops for advanced cancer immunotherapy.
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产品关联
DOI
高影响因子
ANALYTICAL CHEMISTRY
·
2019
·
IF 6.35
Jing Jia,Huilin Wen,Sibo Zhao,Lancheng Wang,Haishi Qiao,Haowen Shen,Ziyi Yu,Bin Di,Lili Xu,Chi Hu
We show how the macrocyclic host cucurbit[8]uril (CB[8]) and a fluorescent dye form a biosensing ensemble while its cavity simultaneously traps tryptophan, the upstream substrate of IDO1 enzymes, therefore providing a label-free method to monitor the activity of IDO1 in real time. Incubation of malignant HeLa and HepG2 cells overexpressing IDO1 with the associative biosensor resulted in its spontaneous uptake and a fluorescence switch-on response in situ, which can be traced to the displacement of tryptophan from CB[8] upon IDO1-catalyzed oxidation. The results, for the first time, establish a supramolecular sensing concept for the detection of intracellular enzymatic activity in live cells, thus allowing direct cell-based analysis and inhibitor screening compatible with commercial instruments including microplate reader, fluorescent microscopy, and flow cytometry.
研究领域:
生物化学
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分子生物学
·
癌症研究
·
细胞生物学
·
分析化学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
·
2025
·
IF 4.3
Hui-Na Luo,Hong-Yuan Yang,Zai-Mei Wang,Jia-Mei Luo,Tong-Tong Zhang,Zeng-Ming Yang
Progesterone (P4) is essential for pregnancy establishment and maintenance. Clinically, P4 is widely used to regulate the menstrual cycle, maintain pregnancy, and treat luteal phase deficiency. However, P4 administration protocols, particularly regarding routes, dosage, and timing remain poorly defined. Although excessive P4 impairs embryo implantation and decidualization in mice, the underlying mechanism remains unclear. Our data show that decidualization in day 8 pregnant mice and artificial decidualization in day 8 pseudopregnant mice are impaired by 4 mg or 8 mg/mouse P4. The mRNA levels of Prl8a2 and Prl3c1, markers of in vitro decidualization are significantly downregulated by 10 or 20 μM P4. The uterine fluorescent signal of indoleamine 2,3-dioxygenase 1 (IDO1) and protein levels of tryptophan 2,3-dioxygenase (TDO) are increased after ovariectomized mice are treated with excessive P4. Treatment of uterine stromal cells with excessive P4 also significantly upregulates the protein levels of IDO1 and TDO, and kynurenine (Kyn) secretion. Epacadostat (IDO1 antagonist) or RU486 (progesterone receptor antagonist) effectively block P4-induced Kyn elevation. The mRNA levels of Prl8a2 and Prl3c1 and the protein levels of BMP2 are significantly inhibited by Kyn. The high-dose of P4 activates the aryl hydrocarbon receptor (AhR) and its downstream targets CYP1A1 and CYP1B1. Under in vitro decidualization, the mRNA levels of Prl8a2 and Prl3c1 are inhibited by 2-OH-E2 and 4-OH-E2, the catalytic products of CYP1A1 and CYP1B1, respectively. CH-223191, a specific AhR antagonist, effectively counteracts the effects of Kyn on Cyp1a1, Cyp1b1, and Prl8a2 expression. Additionally, nucleolar size in stromal cells is increased both in vivo and in vitro following excessive P4 treatment. Our findings suggest that excessive P4 impairs mouse decidualization via the Kyn-AhR pathway.
研究领域:
生殖生物学
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分子内分泌学
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妇产科学
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胚胎植入
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信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Molecular Biomedicine
·
2025
·Vol. 6
·期 1
·1-18
·
IF 10.1
Yao Yu,Liu Yu-ying,Li Jian-feng,Chen Yun-shuo,Shi Lei,Shen Yang,Yang Li-li,Yang Qing
Acute myeloid leukemia (AML), the most common leukemia in adults, exhibits immune escape characteristics like solid tumors. The expression of indoleamine 2,3-dioxygenase 1 (IDO1), a well-recognized immune checkpoint, has been detected in AML blast cells and is associated with poor clinical outcome. Although an imbalance of B cell subpopulations exists in AML patients’ bone marrow microenvironment, the role of B cells and their interaction with IDO1 in AML have yet to be elucidated. Herein, with bioinformatic analysis, we found the close correlations between IDO1 expression and survival and B cell subpopulation proportions in AML patients. Further, our investigation into IDO1 expression and activity, B cell subpopulation proportions and immunosuppressive interleukin-10 (IL-10) level in AML cells and clinical samples revealed significant findings. Using a co-culture system of healthy human PBMCs and AML cell lines, we demonstrated that high IDO1 expression in AML cells could alter the proportions of total B, regulatory B and memory B cells, and increased the level of IL-10. Finally, with the IDO1 inhibitor RY103 designed by our laboratory, we found that IDO1 inhibition had good anti-leukemic effect and restored the abnormal proportions of B cell subpopulations in AML mice. Our study is the first to reveal the modulation of IDO1 on B cell subpopulations in AML, making a significant breakthrough in understanding the immune escape mechanisms of AML. Application of IDO1 inhibitor, such as RY103, targeting the imbalance of B cell subpopulations can lead to innovative treatments for AML.
研究领域:
肿瘤学
·
免疫学
·
血液学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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