EXPERIMENTAL NEUROLOGY
·
2025
·
IF 4.2
Chen-Meng Qiao,Xiao-Yu Ma,Lu-Lu Tan,Yi-Meng Xia,Ting Li,Jian Wu,Chun Cui,Wei-Jiang Zhao,Yan-Qin Shen
Abnormal tryptophan metabolism is closely linked with neurological disorders. Research has shown that indoleamine 2,3-dioxygenase 1 (IDO-1), the first rate-limiting enzyme in tryptophan degradation, is upregulated in Parkinson's disease (PD). However, the precise role of IDO-1 in PD pathogenesis remains elusive. In this study, we administered 1-methyl-tryptophan (1-MT), an IDO-1 inhibitor, intraperitoneally at 15 mg/kg daily for 21 days to PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 30 mg/kg daily for 5 days. Our results show that IDO-1 inhibition improves behavioral performance, reduces dopaminergic neuron loss, and decreases serum quinolinic acid (QA) content and the aryl hydrocarbon receptor (AHR) expression in the striatum and colon. It also alleviates glial-associated neuroinflammation and mitigates colonic inflammation (decreasing iNOS, COX2) by suppressing the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway. Furthermore, IDO-1 inhibition promotes hippocampal neurogenesis (increasing doublecortin positive (DCX + ) cells and SOX2 + cells), which have recently been recognized as key pathological features and potential therapeutic targets in PD, likely through the activation of the BDNF/TrkB pathway. We further explored the gut-brain connection by depleting the gut microbiota in mice using antibiotics. Notably, the neuroprotective effects of IDO-1 inhibition were completely abolished in pseudo-germ-free mice (administrated an antibiotic mixture orally for 14 days prior to 1-MT treatment), highlighting the dependency of 1-MT's neuroprotective effects on the presence of gut microbiota. Finally, we found IDO-1 inhibition corrects the abnormal elevation of fecal short chain fatty acids (SCFAs). Collectively, these findings suggest that IDO-1 inhibition may represent a promising therapeutic approach for PD.
研究领域:
神经科学
·
药理学
·
微生物学
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
·
2019
·
IF 2.431
Ning Wang,Jie Zhang,Qiao Li,Hui Xu,Geng Chen,Zhiyong Li,Difa Liu,Xin Yang
Indoleamine 2,3-dioxygenase (IDO) is one of the important targets for cancer immunotherapy through tryptophan pathway. Recently it has being paid great attention to search potent and safe IDO inhibitor from small-molecule compounds. Picrasma quassioides is a kind of medicinal plant abundant with tryptophan-derived indole alkaloids . By virtual screening and kinetic method for enzymatic analysis, lead compounds with potential IDO inhibitory activity were discovered for the first time from PQAs, the natural alkaloids in Picrasma quassioides . The results based on molecular docking analysis and structure-activity relationship (SAR) study demonstrated that coordinating with ferrous ion on the active site of IDO has a great impact on the inhibition potency, and β -carboline with carboxyl substituted on C-1 is the key pharmacophore for IDO inhibition of PQAs. Enzymatic assay provided further evidence for the effectiveness of β -carboline-1-carboxylic acid, which displayed as the most potent competitive inhibitor of IDO among these PQAs, and is even more potent than the recognized positive control 1-methyl tryptophan. This natural tryptophan-derived alkaloid thus deserved further deep research as a promising IDO modulator for cancer immunotherapy.
研究领域:
药理学
·
肿瘤学
·
植物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Chemistry-X
·
2023
·
IF 6.1
Zhuoting Liu,Yunfang Ping,Lumei Zhang,Jingran Zhang,Ann Van Schepdael,Xu Wang
In this study, a ligand fishing method was developed to screen potential indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors from coffee extracts by immobilization of IDO1 enzyme on amino-modified magnetic nanoparticles combined with UHPLC-Q-TOF-MS/MS analysis. Parameters including enzyme concentration, immobilization time, the pH of glutaraldehyde and the amount of magnetic nanoparticles were optimized. The results indicated that immobilized IDO1 could be reused 5 times and was stable during storage for 7 days. Several IDO1 ligands were captured by incubating immobilized IDO1 with coffee extract, of which 10 showed an obvious difference comparing to non-conjugated bare nanoparticles. In vitro inhibitory activity was further performed by CE analysis, in which ferulic acid and chlorogenic acid had better IDO1 inhibitory activity, with IC 50 value of 113.7 μM and 307.5 μM. These results demonstrate that this method provides an effective platform for identifying and screening IDO1 inhibitors from natural products.
研究领域:
生物化学
·
药物化学
·
分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Xiaoxiao Hu,Qingqing Dou,Peixiao Jiang,Mo Zhang,Jing Wang
The dense extracellular matrix (ECM) and immunosuppressive tumor microenvironment represent two major challenges in the treatment of triple-negative breast cancer (TNBC). To address these obstacles, this study has developed a polymer micelle (NTP) for ECM remodeling and mitigation the immune microenvironment, based on activating endogenous matrix metalloproteinases (MMP) and suppression indoleamine 2,3-dioxygenase (IDO). Through self-assembly technology, this micelle effectively incorporates chemotherapy drugs (camptothecin (CPT) and cinnamaldehyde (CA)), reactive oxygen species (ROS) stimulants, nitric oxide (NO) donor and IDO inhibitor (NLG919), where CPT and CA have been reported to help generating ROS mainly in the mitochondrion. The guanidine group of poly-L-arginine (PArg), as an NO donor, can react with ROS to generate NO. The micelles aim to achieve significant therapeutic outcomes through robust drug penetration and anti-tumor immunity in multimodal therapy. They exhibit remarkable tumor tissue penetration ability, facilitating precise targeting of mitochondria and ROS production stimulation. Building upon this therapeutic foundation, the micellar system achieves in situ NO release, which effectively degrades the primary ECM through the activation of MMPs, while simultaneously promoting tumor cell apoptosis. Furthermore, the encapsulated NLG919 can be released and effectively mitigating the immunosuppressive milieu and triggering anti-tumor immune responses. Experimental results demonstrate that the micelles exhibit significant anti-tumor effects both in vitro and in vivo , accompanied by favorable biocompatibility. This study provides new insights into the application of subcellular targeting drug delivery systems in TNBC treatment, potentially heralding a new breakthrough in TNBC therapy.
研究领域:
肿瘤学
·
药剂学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2024
·
IF 4.5
Ting Wang,Xiufeng Liao,Xiaodi Zhao,Kai Chen,Yangzhonghui Chen,Hui Wen,Dali Yin,Yuchen Wang,Bin Lin,Sen Zhang,Huaqing Cui
Mimicking the transition state of tryptophan (Trp) and O 2 in the enzymatic reaction is an effective approach to design indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitors. In this study, we firstly assembled a small library of 2-substituted benzo-fused five membered heterocycles and found 2-sulfinyl-benzoxazoles with interesting IDO1 inhibitory activities. Next the inhibitory activity toward IDO1 was gradually improved. Several benzoxazoles showed potent IDO1 inhibitory activity with IC 50 of 82–91 nM, and exhibited selectivity between IDO1 and tryptophan 2, 3-dioxygenase (TDO2). Enzyme binding studies showed that benzoxazoles are reversible type II IDO1 inhibitors, and modeling studies suggested that the oxygen atom of the sulfoxide in benzoxazoles interacts with the iron atom of the heme group, which mimics the transition state of Fe-O-O-Trp complex. Especially, 10b can effectively inhibit the NO production in lipopolysaccharides (LPS) stimulated RAW264.7 cells, and it also shows good anti-inflammation effect on mice acute inflammation model of croton oil induced ear edema.
研究领域:
药理学
·
免疫学
·
药物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2018
·Vol. 41
·期 8
·1243-1250
·
IF 1.694
Yunpeng Qi,Renping Wang,Liang Zhao,Lei Lv,Fan Zhou,Tian Zhang,Feng Lu,Hongli Yan,Gengli Duan
Celastrol is well known for its anti-cancer effects, yet its specific mechanisms against colon cancer are still not fully elucidated. In this study, cytotoxic effect of celastrol against HCT116 colon cancer cells was investigated based on cell viability assay and flow cytometry assay, and the possible mechanism was explored using a strategy combining metabolic profiling and targeted metabolite analysis based on ultra performance liquid chromatography (UPLC)/MS. Celastrol was found to inhibit the growth of colon cancer cells and induce apoptosis. Metabolomics analysis revealed characteristic changes in metabolic profiles of the colon cancer cells, revealing altered levels of amino acids, carnitine, and lipid markers. Most interestingly, with the assistance of targeted metabolite analysis, tryptophan (Trp) level was significantly increased whereas kynurenine (Kyn) level was decreased in colon cancer cells after celastrol treatment, together with markedly declined Kyn/Trp ratios. Western blot analysis revealed that expression of indoleamine 2,3-dioxygenase (IDO), the enzyme catalyzing Trp to generate Kyn, was dramatically inhibited in colon cancer cells after celastrol treatment, with a dose-dependent manner. These results suggest that suppression of IDO expression and tryptophan catabolism may be part of the mechanisms of celastrol in its cytotoxic effect against HCT116 colon cancer cells. This study provided scientific basis for further development of celastrol on treating colon cancer.
研究领域:
肿瘤学
·
药理学
·
代谢组学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Haisi Wu,Xianbao Sun,Kaiming Li,Jinyu Li,Hui Jiang,Dan Yan,Ya Lin,Yan Ding,Yawen Lu,Xiaole Zhu,Xufeng Chen,Xiaolin Li,Gaolin Liang,Huae Xu
Paclitaxel (PTX) is a first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC) but it can induce indoleamine 2,3-dioxygenase (IDO) activation, which severely lowers down its immuno-chemotherapeutic effect. To address this issue, a smart peptide hydrogelator Nap–Phe–Phe–Phe–Lys–Ser–Thr–Gly–Gly–Lys–Ala–Pro–Arg–OH ( Nap-T ), which co-assembles with PTX and an IDO inhibitor GDC0919 to form a hydrogel GP@Gel Nap-T, is rationally designed. Upon specific phosphorylation by pyruvate kinase M2 (PKM2), an overexpressed biomarker of NSCLC, Nap-T is gradually converted to Nap–Phe–Phe–Phe–Lys–Ser–Thr(H 2 PO 3 )–Gly–Gly–Lys–Ala–Pro–Arg–OH ( Nap-Tp ), leading to dehydrogelation and sustained release of PTX and GDC0919 within NSCLC tissues. The released PTX exerts chemotherapy on NSCLC cells as well as immunogenic cell death induction, while GDC0919 promotes the immuno-chemotherapeutic effect of PTX through IDO inhibition. We find that GP@Gel Nap-T enhances the infiltration of tumor-infiltrating immune cells and reduces the number of immunosuppressive cells in either tumor tissues or tumor-draining lymph nodes, thus enhancing the immuno-chemotherapy of PTX toward NSCLC. With this PKM2-responsive drug release strategy, the smart peptide hydrogel platform might be applied for NSCLC treatment in clinic in near future.
研究领域:
肿瘤学
·
药理学
·
免疫学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Microbiome
·
2023
·Vol. 11
·期 1
·1-20
·
IF 15.5
Sun Penghao,Wang Mengli,Liu Yong-Xin,Li Luqi,Chai Xuejun,Zheng Wei,Chen Shulin,Zhu Xiaoyan,Zhao Shanting
Background Aberrant tryptophan (Trp)-kynurenine (Kyn) metabolism has been implicated in the pathogenesis of human disease. In particular, populations with long-term western-style diets are characterized by an excess of Kyn in the plasma. Host-gut microbiota interactions are dominated by diet and are essential for maintaining host metabolic homeostasis. However, the role of western diet-disturbed gut microbiota-colonocyte interactions in Trp metabolism remains to be elucidated. Results Here, 4-week-old mice were fed with a high-fat diet (HFD), representing a typical western diet, for 4 weeks, and multi-omics approaches were adopted to determine the mechanism by which HFD disrupted gut microbiota-colonocyte interplay causing serum Trp-Kyn metabolism dysfunction. Our results showed that colonocyte-microbiota interactions dominated the peripheral Kyn pathway in HFD mice. Mechanistically, persistent HFD-impaired mitochondrial bioenergetics increased colonic epithelial oxygenation and caused metabolic reprogramming in colonites to support the expansion of Proteobacteria in the colon lumen. Phylum Proteobacteria -derived lipopolysaccharide (LPS) stimulated colonic immune responses to upregulate the indoleamine 2,3-dioxygenase 1 (IDO1)-mediated Kyn pathway, leading to Trp depletion and Kyn accumulation in the circulation, which was further confirmed by transplantation of Escherichia coli ( E.coli ) indicator strains and colonic IDO1 depletion. Butyrate supplementation promoted mitochondrial functions in colonocytes to remodel the gut microbiota in HFD mice, consequently ameliorating serum Kyn accumulation. Conclusions Our results highlighted that HFD disrupted the peripheral Kyn pathway in a gut microbiota-dependent manner and that the continuous homeostasis of gut bacteria-colonocytes interplay played a central role in the regulation of host peripheral Trp metabolism. Meanwhile, this study provided new insights into therapies against western diet-related metabolic disorders.
Video Abstract
研究领域:
营养学
·
微生物学
·
代谢学
·
免疫学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2022
·Vol. 41
·期 1
·1-17
·
IF 12.658
Fan Qingxin,Zuo Jing,Tian Hailong,Huang Canhua,Nice Edouard C.,Shi Zheng,Kong Qingquan
Background The high postoperative recurrence rate and refractoriness of relapsed tumors are still a conundrum for the clinical management of osteosarcoma (OS). New therapeutic options are urgently needed. Depriving the nourishment of myeloid-derived suppressor cells is a novel strategy to improve the immunosuppressive tumor microenvironment for enhanced OS therapy.Methods We synthesized a hyaluronic acid (HA)-modified metal–organic framework for combinational chemotherapy and immunotherapy of OS. Zeolitic Imidazolate Framework-8 (ZIF-8) was prepared by a one-pot synthetic method, Gemcitabine (Gem) and D-1-Methyltryptophan (D-1-MT) were loaded into the ZIF-8 during the synthesis process to make ZIF-8@Gem/D-1-MT nanoparticles (NPs). The end product (HA/ZIF-8@Gem/D-1-MT NPs) was obtained by HA modification on the surface of ZIF-8@Gem/D-1-MT NPs. The obtained HA/ZIF-8@Gem/D-1-MT NPs have excellent potential as a drug delivery vector for chemotherapy and immunotherapy in vitro and vivo.Results The results indicate that HA/ZIF-8@Gem/D-1-MT NPs were readily taken up by OS cells, and that the Gem and D-1-MT were effectively released into the acidic environment. The HA/ZIF-8@Gem/D-1-MT NPs could efficiently decrease OS cell viability (proliferation, apoptosis, cell cycle, migration and invasion). And HA/ZIF-8@Gem/D-1-MT NPs could reactivate antitumor immunity by inhibiting indoleamine 2,3 dioxygenase and myeloid-derived suppressor cells. Furthermore, animal experiments confirmed that HA/ZIF-8@Gem/D-1-MT NPs could induce intratumoral immune responses and inhibit tumor growth. Additionally, HA/ZIF-8@Gem/D-1-MT NPs have a good safety profile.Conclusion sOur findings demonstrate that the combination of Gem with D-1-MT brings new hope for the improved treatment of OS, while the generation of the nanosystem has increased the application potential and flexibility of this strategy.
研究领域:
癌症研究
·
纳米技术
·
药学
·
免疫学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
MedComm
·
2024
·Vol. 5
·期 5
·e555
·
IF 10.7
Heng Liang,Jiani Zhan,Yunqiu Chen,Zikang Xing,Zhen Ning Tony He,Yuying Liu,Xuewen Li,Yijia Chen,Zhiyao Li,Chunxiang Kuang,Dan Yang,Qing Yang
Indoleamine 2,3-dioxygenase 1 (IDO1), the key enzyme in the catabolism of the essential amino acid tryptophan (Trp) through kynurenine pathway, induces immune tolerance and is considered as a critical immune checkpoint, but its impacts as a metabolism enzyme on glucose and lipid metabolism are overlooked. We aim to clarify the potential role of IDO1 in aerobic glycolysis in pancreatic cancer (PC). Analysis of database revealed the positive correlation in PC between the expressions of IDO1 and genes encoding important glycolytic enzyme hexokinase 2 (HK2) , pyruvate kinase (PK) , lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1) . It was found that IDO1 could modulate glycolysis and glucose uptake in PC cells, Trp deficiency caused by IDO1 overexpression enhanced glucose uptake by stimulating GLUT1 translocation to the plasma membrane of PC cells. Besides, Trp deficiency caused by IDO1 overexpression suppressed the apoptosis of PC cells via promoting glycolysis, which reveals the presence of IDO1–glycolysis–apoptosis axis in PC. IDO1 inhibitors could inhibit glycolysis, promote apoptosis, and exhibit robust therapeutic efficacy when combined with GLUT1 inhibitor in PC mice. Our study reveals the function of IDO1 in the glucose metabolism of PC and provides new insights into the therapeutic strategy for PC.
研究领域:
癌症生物学
·
代谢途径
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Jiayi Bian,Yingjie Xu,Minghao Sun,Zerui Ma,Hao Li,Changrui Sun,Fei Xiong,Xiaopeng Zhao,Wenjing Yao,Yue Chen,Yuanyuan Ma,Xikuang Yao,Shenghong Ju,Wenpei Fan
Accurate imaging and precise treatment are critical to controlling the progression of pancreatic cancer. However, current approaches for pancreatic cancer theranostics suffer from limitations in tumor specificity and invasive surgery. Herein, a pancreatic cancer-specific phototheranostic modulator (AuHQ) dominated by aggregation-induced emission (AIE) luminogens-tethered gold nanoparticles is meticulously designed to facilitate prominent fluorescence-photoacoustic bimodal imaging-guided photothermal immunotherapy. Once reaching the pancreatic tumor microenvironment (TME), the peptide Ala-Gly-Phe-Ser-Leu-Pro-Ala-Gly-Cys (AGFSLPAGC) linkage within AuHQ can be specifically cleaved by the overexpressed enzyme Cathepsin E (CTSE), triggering the dual self-assembly of AuNPs and AIE luminogens. The aggregation of AuNPs mediated by enzymatic cleavage results in potentiated photothermal therapy (PTT) under near-infrared (NIR) laser irradiation, induced immunogenic cell death (ICD), and enhanced photoacoustic imaging. Simultaneously, AIE luminogen aggregates formed by hydrophobic interaction can generate AIE fluorescence, enabling real-time and specific fluorescence imaging of pancreatic cancer. Furthermore, coadministration of an indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor with AuHQ can address the limitations of PTT efficacy imposed by the immunosuppressive TME and leverage the synergistic potential to activate systemic antitumor immunity. Thus, this well-designed phototheranostic modulator AuHQ facilitates the intelligent enzymatic dual self-assembly of imaging and therapeutic agents, providing an efficient and precise approach for pancreatic cancer theranostics.
研究领域:
生物医学工程
·
癌症治疗
·
纳米技术
·
成像科学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Qilin Li,Huiling Fan,Yunruo Xu,Miaodeng Liu,Jia Liu,Luming Xu,Meizhen Zou,Qian Cheng,Yan Zhang,Tao Liang,Lin Shi,Xianluo Hu,Lin Wang,Zheng Wang
Photothermal and photodynamic therapies (PTT and PDT) generating regional hyperpyrexia or reactive oxygen species (ROS) not only kill tumors within irradiated site, but also potentially suppress metastatic tumors far away from irradiated site by activation of antitumor immunity through inducing immunogenic cell death (ICD) (termed as “abscopal effect”). However, mono-PTT or mono-PDT are generally insufficient to produce intensive and long-lasting “abscopal effect”. Moreover, abundant immune suppressors within tumor microenvironment can offset ICD-induced antitumor effects that further cripple phototherapeutic efficacy. Towards effective eradication of both primary and metastatic tumors, it is necessary to combine photothermal and photodynamic antitumor effects as well as reverse immunosuppressive tumor microenvironment. Here, we report a hollow germanium nanosphere (HGNs) with both favorable photothermal and photodynamic effects. HGNs under near-infrared (NIR) irradiation generated hyperpyrexia and intracellular ROS, promoting ICD of tumor cells. Notably, HGNs-mediated photothermal and photodynamic effects reduce the expression of immunosuppressive indoleamine-2,3-dioxygenase (IDO), stemness- and invasion/migration-related genes. In preclinical tumor models, HGNs drives antitumor immunity by promoting effector T-cell infiltration and reducing immunosuppressive regulatory T cells (Tregs) under NIR, thus eradicating both primary and distant tumors along with extension of animal survival. Thus, with good biosafety, HGNs demonstrates a great clinically-translational potential.
研究领域:
癌症治疗
·
纳米技术
·
免疫疗法
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
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