Phenomics
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2026
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IF 5.5
Li Zhiyao,Fang Mengyuan,Wang Yu,Chen Yunqiu,Liu Yuying,Chen Yijia,Li Xuewen,Meng Fangzhou,Qian Xiaoyang,He Zhen Ning Tony,Yang Qing
Prolonged immunosuppression is a major risk factor for sepsis death. The mechanism of sepsis-associated immunosuppression remains unclear, hindering timely and targeted immunotherapy. The immunomodulatory enzyme, indoleamine-2,3-dioxygenase 1 (IDO1), is overactivated in patients with sepsis; however, its role in sepsis-associated immunosuppression remains unclear. In this study, we defined the time window when cecal ligation puncture (CLP) mice, a gold-standard sepsis model, entered the immunosuppressive state and confirmed elevated IDO1 activity during this phase. The IDO1 inhibitor prevented the occurrence of immunosuppression in CLP mice by decreasing the concentration of interleukin-10 (IL-10), the number of regulatory T cells and myeloid-derived suppressor cells, and increasing the proportion of M1 macrophages, which led to clearance of pathogenic bacteria in the peritoneal cavity. The IDO1 inhibitor enhanced resistance to infection and improved the survival of septic mice during secondary infection with Staphylococcus aureus . Finally, we explored the potential role of IDO1 in macrophages, key participants in the progression of sepsis. IDO1 preferentially promoted IL-10 production in septic macrophages through the aryl hydrocarbon receptor–STAT3 axis. In macrophages, IDO1 inhibited the mammalian target of rapamycin pathway by depleting ambient tryptophan, leading to the downregulation of the mitochondrial biogenesis regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and the metabolic reprogramming mediator hypoxia-inducible factor 1-alpha (HIF-1α). The downregulation of PGC-1α and HIF-1α inhibited mitochondrial biogenesis and glycolysis, respectively, both of which were essential for immune defense. These results demonstrate that IDO1 is a crucial mediator of sepsis-associated immunosuppression, and that targeting IDO1 could serve as a therapeutic strategy for sepsis.
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高影响因子
JOURNAL OF CHROMATOGRAPHY A
·
2021
·
IF 4.759
Zhuoting Liu,Chunling Wang,Xu Wang,Ann Van Schepdael
Indoleamine 2,3-dioxygenase 1 (IDO1) has been shown to play an important role in the immune escape process of tumors, and therefore is considered as a promising target for tumor immunotherapy. In this study, off-line and on-line capillary electrophoresis methods were developed for IDO1 inhibitors screening from natural product extracts. The optimized separation conditions of CE were achieved with 32 mM sodium tetraborate (pH 9.22) as background electrolyte, using a separation voltage of 21 kV. The off-line CE method was verified by the determination of enzymatic kinetic parameters and inhibitory mechanisms of two known inhibitors. A partial filling on-line CE method combined with rapid polarity switching was used for rapid screening of IDO1 inhibitors. The whole reaction and separation process was completed within 5 min. The on-line CE screening results showed that six of 18 natural products had inhibitory effect on IDO1, namely Carthamus tinctorius, Schisandra chinensis , Raisin, Coffee, Hawthorn and Radix angelicae sinensis. The results of on-line CE experiments were consistent with the off-line results, which proved the practicability and effectiveness of the method for inhibitors screening.
研究领域:
生物化学
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药物化学
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肿瘤学
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PubMed
高影响因子
ACS Applied Bio Materials
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2019
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IF 0
Zaizai Dong,Chuanhao Tang,Zhen Zhang,Wei Zhou,Rong Zhao,Lina Wang,Jiachao Xu,Yayun Wu,Jiang Wu,Xing Zhang,Li Xu,Libo Zhao,Xiaohong Fang
Exosomes, which are 30–150 nm extracellular vesicles containing a variety of biomolecules (i.e., proteins, RNA, DNA, and lipids), have emerged as important analytes in liquid biopsy. Although exosome detection offers a valuable chance to understand disease status in a multidimensional manner, comprehensive analysis of different exosomal biomolecules with limited specimens remains a challenge. Herein, we introduced an aptamer-based PCR (polymerase chain reaction) platform and realized highly sensitive detection of CD63 protein positive exosomes as low as 50 particles/μL. More importantly, simultaneous analysis of exosomal RNA and surface protein is available using this method. In a proof of concept experiment, simultaneous detection of two immunotherapy-related biomarkers, programmed death-ligand 1 (PD-L1) protein and indoleamine 2,3-dioxygenase 1 (IDO1) mRNA, was demonstrated with clinical samples. Our method provides a strategy for the comprehensive analysis of exosomes, with the advantages of high sensitivity and practicability.
研究领域:
生物技术
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分子生物学
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癌症研究
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医学诊断
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DOI
PubMed
Advanced Science
·
2024
·
IF 14.3
Jiaxing Huang,Xiaotang Wang,Na Li,Wei Fan,Xingran Li,Qian Zhou,Jiangyi Liu,Wanqian Li,Zhi Zhang,Xiaoyan Liu,Shuhao Zeng,Hui Yang,Meng Tian,Peizeng Yang,Shengping Hou
Activated microglia in the retina are essential for the development of autoimmune uveitis. Yin-Yang 1 (YY1) is an important transcription factor that participates in multiple inflammatory and immune-mediated diseases. Here, an increased YY1 lactylation in retinal microglia within in the experimental autoimmune uveitis (EAU) group is observed. YY1 lactylation contributed to boosting microglial activation and promoting their proliferation and migration abilities. Inhibition of lactylation suppressed microglial activation and attenuated inflammation in EAU. Mechanistically, cleavage under targets & tagmentation （CUT&Tag） analysis revealed that YY1 lactylation promoted microglial activation by regulating the transcription of a set of inflammatory genes, including STAT3, CCL5, IRF1, IDO1 , and SEMA4D . In addition, p300 is identified as the writer of YY1 lactylation. Inhibition of p300 decreased YY1 lactylation and suppressed microglial inflammation in vivo and in vitro. Collectively, the results showed that YY1 lactylation promoted microglial dysfunction in autoimmune uveitis by upregulating inflammatory cytokine secretion and boosting cell migration and proliferation. Therapeutic effects can be achieved by targeting the lactate/p300/YY1 lactylation/inflammatory genes axis.
研究领域:
免疫学
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神经科学
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分子生物学
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眼科学
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PubMed
高影响因子
Journal of Advanced Research
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2026
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IF 17.1
Yuting Zhang,Ruopeng Yin,Wang Dong,Li Sun,Tao Wang,Jingzu Sun,Huanqin Dai,Yanliang Bi,Liangliang Wang,Hongwei Liu
Introduction Sepsis is a life-threatening syndrome of organ dysfunction driven by a dysregulated immune response. Effective therapeutic strategies to restore immune homeostasis remain limited. Hypoacylated lipooligosaccharides (ALOS) from Akkermansia muciniphila have emerged as potential immunomodulatory postbiotics, yet their therapeutic potential in sepsis and the underlying mechanisms remain unexplored. Objectives This study aims to investigate whether ALOS confers protection in experimental models of sepsis induced by toxic lipopolysaccharides (LPS) or cecal ligation and puncture (CLP), and the mechanism by which ALOS exerts its anti-inflammatory and regulatory effects. Methods In LPS or CLP-induced mouse sepsis models and a porcine sepsis model, ALOS (0.2 mg/kg, i.p.) was administered once every two days before challenge or half an hour post-surgery. Survival rates, physiological and biochemical parameters were assessed. Based on 16S rRNA gene amplicon sequencing and barrier function assessment, the changes of the colonic microbiota and metabolites and anti-inflammatory capacity were analyzed. The anti-inflammatory and immunomodulatory mechanisms of ALOS were investigated through dendritic cell phenotyping, transcriptomic analysis, inhibitor assays, and conditioned medium experiments. Finally, the safety of ALOS was evaluated in C57BL/6J mice following one-week administration (0.2 mg/kg, i.p.). Results ALOS pretreatment significantly suppresses sepsis, reduces the proportion of pro-inflammatory Th17 cells, and increases regulatory T cells (Treg). Mechanistically, ALOS induced semi‑mature dendritic cells with upregulated IDO1 expression, leading to enhanced production of kynurenine (Kyn). Kyn activated the aryl hydrocarbon receptor (AhR) to drive Treg differentiation. The protective effect of ALOS was completely reversed by NLG919, whereas Kyn administration mimicked the therapeutic benefit. ALOS also produced therapeutic protection on sepsis. In a porcine sepsis model, pretreatment of ALOS exerted systemic anti‑inflammatory effects and protected multiple organs. Conclusion This study highlights the protective role of ALOS in sepsis and identifies the IDO1-Kyn-AhR immune axis as the major underlying mechanism.
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PubMed
高影响因子
CANCER RESEARCH
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2025
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IF 16.6
Zhang Shijie,Wang Siyu,Wang Yixue,Zhou Tianle,Yang Jiaxin,Xu Jingxue,Li Gen,Zhang Yunyan,Wang Xiaoyuan,Yin Hang
Radioresistance is one of the primary causes of treatment failure in non-small cell lung cancer (NSCLC). In this study, we identified PRMT3 within tumors as a critical mediator impairing both radiotherapy sensitivity and T-cell anti-tumor activity. In tumor cells, PRMT3 mediated arginine methylation of transcription factor TFAP2A, enhancing its binding to the IDO1 promoter. Methylated TFAP2A exhibited a prolonged half life, increased nuclear localization, and enhanced dimer formation, which ultimately led to heightened IDO1 expression that enhanced synthesis of kynurenine (Kyn). The elevated Kyn production boosted radioresistance in tumor cells and suppressed the infiltration and function of CD8+ T cells by activating aryl hydrocarbon receptors (AhR). Interestingly, combined pharmacological inhibition of PRMT3 and IDO1 effectively disrupted the TFAP2A-IDO1-Kyn axis, overcoming radioresistance, activating anti-tumor immunity, and ultimately eradicating tumors. In conclusion, these findings delineate PRMT3-mediated Kyn metabolism as a mechanism of radioresistance and immune evasion in NSCLC, offering valuable insights for potential interventions for treating lung cancer patients.
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PubMed
高影响因子
PHYTOMEDICINE
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2026
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IF 11.3
Xiaoya Li,Xingyu Liu,Qinbin Ye,Shengchen Wang,Xiaoyu Xi,Jingyi Jiang,Xiaoshuang Mao,Meirong Fang,Wen Jin,Cheng Xiao
EZP enhances bone protection of MTX in RA by bidirectionally regulating OC and OB. • EZP augments the osteoprotective effect of MTX by IDO1-KYN-AhR pathway. • Salidroside and ferulic acid from EZP are responsible for synergizing with MTX. • We provide a promising integrative strategy for managing bone disorders in RA. Progressive joint destruction and systemic bone loss are key factors contributing to disability and secondary osteoporosis in rheumatoid arthritis (RA). However, current clinical drugs, including first-line methotrexate (MTX), provide limited bone protection. Enhancing the regulatory effect of MTX on RA bone homeostasis through combination with traditional Chinese medicine (TCM) may offer a new perspective for RA treatment. This study investigated whether Erzhi Pill (EZP), a kidney-tonifying TCM formula, enhances MTX efficacy in regulating bone homeostasis in RA via the IDO1-KYN-AhR signaling pathway. Using primary osteoblast/osteoclast models and a kidney deficiency collagen-induced arthritis (KD-CIA) rat model, we demonstrated that the MTX+EZP combination was superior to MTX monotherapy in promoting osteoblast differentiation/function, suppressing osteoclastogenesis, and mitigating bone destruction and loss in KD-CIA rats. These effects were associated with the restoration of suppressed IDO1-KYN-AhR signaling activity. Furthermore, siRNA-mediated knockdown or pharmacological inhibition of IDO1 or AhR reversed the regulatory effects of MTX+EZP on osteoblast-osteoclast differentiation/function and its bone-protective actions in KD-CIA rats. Finally, salidroside and ferulic acid were identified as the potential active compounds in EZP responsible for synergizing with MTX. In summary, our findings demonstrate that EZP enhances the efficacy of MTX in regulating RA bone homeostasis by activating the IDO1-KYN-AhR signaling pathway, representing a promising integrative strategy for managing RA-induced bone metabolism disorders.
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高影响因子
BIOORGANIC CHEMISTRY
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2020
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IF 4.831
Qing-Zhu Fan,Ji Zhou,Yi-Bao Zhu,Lian-Jun He,Dong-Dong Miao,Sheng-Peng Zhang,Xiao-Ping Liu,Chao Zhang
Targeting the Trp-Kyn pathway is an attractive approach for cancer immunotherapy. Thioredoxin reductase (TrxR) enzymes are reactive oxygen species (ROS) modulators that are involved in the tumor cell growth and survival processes. The 4-phenylimidazole scaffold is well-established as useful for indoleamine 2,3-dioxygenase 1 (IDO1) inhibition, while piperlongumine (PL) and its derivatives have been reported to be inhibitors of TrxR. To take advantage of both immunotherapy and TrxR inhibition, we designed a first-generation dual IDO1 and TrxR inhibitor ( ZC0101 ) using the structural combination of 4-phenylimidazole and PL scaffolds. ZC0101 exhibited better dual inhibition against IDO1 and TrxR in vitro and in cell enzyme assays than the uncombined forms of 4-phenylimidazole and PL. It also showed antiproliferative activity in various cancer cell lines, and a selective killing effect between normal and cancer cells. Furthermore, ZC0101 effectively induced apoptosis and ROS accumulation in cancer cells. Knockdown of TrxR1 and IDO1 expression induced cellular enzyme inhibition and ROS accumulation effects during ZC0101 treatment, but only reduced TrxR1 expression was able to improve ZC0101 ′s antiproliferation effect. This proof-of-concept study provides a novel strategy for cancer treatment. ZC0101 represents a promising lead compound for the development of novel antitumor agents that can also be used as a valuable probe to clarify the relationships and mechanisms of cancer immunotherapy and ROS modulators.
研究领域:
肿瘤学
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药理学
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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
Applied Materials Today
·
2022
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IF 8.663
Jiulong Zhang,Xiaoyan Sun,Lin Liu,Xiufeng Zhao,Chunrong Yang,Kexin Li,Haiyang Hu,Mingxi Qiao,Dawei Chen,Xiuli Zhao
Increase extracellular adenosine triphosphate (ATP, a necessary eat me signal for ICD) is a facile way to amplify immunogenic cell death (ICD) cascade for cancer immunotherapy. However, it is still challenging for intratumoral delivery ATP due to complicated enzyme environment in the whole body. Furthermore, tumor immunosuppressive microenvironment (TIM) also hampers the function of mature DCs and limit the activation of immune response. To overcome these drawbacks, a tumor-permeated ATP-based immunogenic cell death amplifier (NABP@SNCs) is fabricated for the first time. (Phenylboronic acid-polyethylene glycol-phenylboronic acid) PBA-PEG-PBA stabilized ultrasmall platinum nanoparticles (ABP) is constructed and interacted with ATP through borate ester bond. Indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor NLG919 and ABP are co-wrapped with MMP-2 sensitive framework to form NABP@SNCs. NABP@SNCs can not only protect ATP degradation but also release small sized ABP under MMP-2 microenvironment for tumor penetration. Interestingly, ATP can also be released into extracellular regions in tumor acidic pH and act as ‘eat me signal’ for DCs maturation. Synergistically ICD activation by BP (PBA-PEG-PBA stabilized ultrasmall platinum nanoparticles) and TIM reversal by NLG919 can facilitate T lymphocyte cells infiltration for immune response. NABP@SNCs can significantly regress tumor growth and reduce pulmonary metastasis for improved cancer immunotherapy.
研究领域:
肿瘤学
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免疫学
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纳米医学
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高影响因子
Advanced Healthcare Materials
·
2019
·Vol. 8
·期 13
·1900174
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IF 6.27
Haishi Qiao,Jing Jia,Haowen Shen,Sibo Zhao,Enping Chen,Wei Chen,Bin Di,Chi Hu
Nanosystems responsive to tumor-specific enzymes are considered as a highly attractive approach to intracellular drug release for targeted cancer therapy. Mesoporous silica nanoparticles are capped with tryptophan-mediated cucurbit[8]uril complex with Fe 3 O 4 to minimize the premature drug leakage while being able to deliver the payload on demand at the target tissue. The supramolecular interaction between tryptophan and cucurbit[8]uril is disrupted in the presence of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme (abundant in the tumor intracellular microenvironment), which catalyzes the metabolism of tryptophan into N -formylkynurenine, resulting in the disassembly of the “gate-keeper” of the nanocarriers and intracellular release of therapeutics exclusively in tumor cells. The drug release from the nanocarrier with high selectivity to overexpressed IDO1 enzyme induces significant cytotoxicity against HepG2 cells in vitro, as well as the superior antitumor effects in vivo. This robust supramolecular nanosystem with sophisticated structure and property provides a promising platform for intracellular drug release targeting the intrinsic microenvironmental enzyme inside the tumor cells.
研究领域:
纳米技术
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药物递送系统
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癌症治疗
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酶响应纳米载体
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超分子化学
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DOI
PubMed
高影响因子
LIFE SCIENCES
·
2019
·
IF 3.448
Yun-Feng Zhou,Li Feng,Xin-Min Liu,Xue Tao,Li-Sha Wang,Meng-Di Zhang,Zhi Wang,Shan-Guang Chen,Qi Chang
Aims The present study aims to investigate the impacts of olfactory bulbectomy (OBX) on urinary metabolic profile and tryptophan metabolites in prefrontal cortex (PFC) of rats, and to explore the regulation effects of fluoxetine. Main methods OBX model was developed by aspiration of olfactory bulbs. After fluoxetine treatment (10 mg/kg) for 14 days, urine samples were collected and behavior tests were applied. Tryptophan (TRP) metabolites and neurotransmitters in PFC were determined by prominence ultrafast liquid chromatography-QTRAP-mass spectrometry, and tryptophan hydroxylase 2 (TPH2) and indoleamine-2,3-dioxygenase 1 (IDO1) were evaluated by western blot. Urinary metabolites were analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry-based metabonomics strategy. Key finding OBX rats showed hyperlocomotion in open field, hyperactivity in open arm and despair status, and fluoxetine reserved these behavioral abnormalities. The levels of TRP, 5-HIAA, 5-HIAA/5-HT ratio and DA increased, while kynurenine and 5-HT decreased in PFC of OBX rats. The activities of TPH2 and IDO1were inhibited after OBX. Twenty-six altered metabolites were identified as potential biomarkers in OBX rats involved in tryptophan metabolism, gut microbiota metabolism, energy metabolism, purine metabolism, ascorbate and aldarate metabolism, and tyrosine metabolism. Among them, 15 abnormal metabolites were corrected by fluoxetine to some extent. Significance Our results revealed that urinary metabolic profile changed greatly in OBX rats, and identified biomarkers might be helpful for the diagnosis of agitated depression. The regulation effects of fluoxetine on urinary metabolic profile and tryptophan metabolites in PFC might contribute to its antidepressant action in OBX rats.
研究领域:
神经科学
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药理学
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代谢组学
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PubMed
高影响因子
NEUROSCIENCE LETTERS
·
2026
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IF 2.2
XinQun Xu,QuanLan Wang,Long Wang,WenQiang Cheng,Fei Li,HuanBing Liu,YuangBing Guo
Objective To investigate the regulatory mechanism of IDO1 on brain tissue damage in Alzheimer’s disease (AD) mice. Methods APP/PS1 mice (AD model mice) and C57BL/6J mice were treated with IDO1 inhibitor 1-MT. Behavioral changes were assessed using the open field test, and histopathological changes were analyzed using HE staining, Nissl staining, and transmission electron microscopy. TUNEL staining and immunofluorescence were used to detect cell apoptosis and the expression of IDO1 and GFAP, respectively. Metabolomics was analyzed using liquid chromatography-mass spectrometry. An in vitro AD cell model was established, and inflammatory factor levels were measured using ELISA/qPCR, while NF-κB pathway activation was assessed using WB. Results In vivo experiments showed that compared with the model group mice, 1-MT intervention improved behavioral abnormalities in AD mice, reduced hippocampal tissue damage, decreased neuronal apoptosis, and downregulated the expression of IDO1 and GFAP. In vitro experiments demonstrated that interfering with IDO1 could decrease the levels of IL-1β, TNF-α, and IL-6, reduce GFAP expression, and inhibit p65 phosphorylation. Conclusion Interfering with IDO1 can inhibit the NF-κB pathway, reduce the release of inflammatory factors, and improve brain tissue damage in AD mice.
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高影响因子
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