Neuropsychiatric Disease and Treatment
·
2022
·
IF 2.989
Kun Zhang,Ran Liu,Yuan Gao,Wen Ma,Weidong Shen
Background Neuroinflammation is an important pathological mechanism of depression that leads to an increase in indoleamine-2,3-dioxygenase (IDO) activity and NMDAR activation. This study aimed to observe the effects of electroacupuncture on depression-like behaviour in lipopolysaccharide (LPS)-treated rats and the underlying mechanism.Methods Wistar rats were intraperitoneally administered LPS (0.5 mg/kg) for 7 consecutive days to establish a depression model. Electroacupuncture treatment was administered 1 hour after daily LPS injection. The open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were used to evaluate the depressive-like behaviours. IL-1β, IL-6, and TNF-α levels were determined by enzyme-linked immunosorbent assay (ELISA); Trp, 5-hydroxytryptamine (5-HT), kynurenine (Kyn) and quinolinic acid (Quin) were detected by ultra-high-performance liquid chromatography-tandem mass spectrometry; and N-methyl-D-aspartate receptor (NMDAR) protein and mRNA were assessed by Western blot and real-time qPCR.Results The results showed that electroacupuncture treatment successfully corrected LPS-induced depressive-like behaviour, reduced the inflammatory factor (IL-1β, IL-6 and TNF-α) levels in the blood and hippocampus, prevented IDO over-activation and recovered NR2B expression after challenge by LPS.Conclusion Electroacupuncture treatment provided protection against LPS-induced depressive-like behaviour, and the associated mechanisms may be related to inhibiting the inflammatory response, regulating the IDO-mediated tryptophan-degrading pathway, and inhibiting NR2B activation.
研究领域:
神经科学
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药理学
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免疫学
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行为科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2023
·
IF 14
Ping Huang,Yao Yang,Wenyan Wang,Zimu Li,Nansha Gao,Hongzhong Chen,Xiaowei Zeng
Insufficient immune stimulation and stubborn immune resistance are the critical factors limiting tumor immunotherapy. Here, we report a multifunctional nanoprodrug platform with self-driven indoximod (IND) release and oxidative stress amplification. The aim is to awaken immune responses and block the indoleamine 2,3-dioxygenase (IDO) pathway through a combination of ferroptosis , photothermal therapy, and immunotherapy. This nanosystem improved the delivery efficiency of IND due to click chemistry linked ROS responsive prodrug and self-driven drug release. Meanwhile, the tactic of simultaneously increasing ROS and eliminating GSH amplified oxidative stress and strengthened ferroptosis, which further enhanced immunogenicity along with polydopamine-based photothermal therapy. IDO immunization combined with ferroptosis as well as photothermal therapy not only stimulated immune response, but also reversed immune suppression with enhanced immune memory . Therefore, primary tumor, distant tumor, and cancer metastasis were inhibited. This study provides a perspective on immunotherapeutics for cancer treatment.
研究领域:
癌症治疗
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纳米医学
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免疫学
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药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INFLAMMATION
·
2020
·Vol. 43
·期 5
·1780-1788
·
IF 3.212
Zhang Liming,Huang Yang,Cui Xiaoxiao,Tan Xiao,Zhu Ying,Zhou Wenjun,Wang Chaokui,Yuan Gangxiang,Cao Qingfeng,Su Guannan,Kijlstra Aize,Yang Peizeng
Previous studies have pointed out that indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme initiating tryptophan metabolism, plays a role in the regulation of the immune system. This project was designed to investigate the potential role of IDO in monocyte-derived dendritic cells (moDCs) obtained from active Vogt-Koyanagi-Harada (VKH) disease patients. In this study, we found that the IDO mRNA expression and enzyme activity were increased in active VKH patients as compared with healthy controls and patients in remission. To investigate the role of IDO in immune regulation, an effective inhibitor 1-methyl-L-tryptophan (1-MT) was used to suppress its activity in DCs. The results showed that inhibition of IDO with 1-MT significantly decreased the expression of DC marker CD86. IDO inhibition did not affect the cytokine production of IL-6, IL-1β, TNF-α, IL-10, and TGF-β in DCs. Downregulation of IDO in DCs also led to the reduction of regulatory T (Treg) cells and an increased CD4 + T cell proliferation. Treatment with 1-MT did not affect the phosphorylation of the MAPK pathway in DCs. In general, our study suggests that IDO may play an important role in the pathogenesis of VKH disease by regulating DC and CD4 + T cell function. Tryptophan deficiency and kynurenine accumulation may account for the complicated effects of IDO. Further research is needed to study the precise tryptophan metabolites that may limit immune responses in VKH disease.
研究领域:
免疫学
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眼科
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF POLYMER SCIENCE
·
2022
·Vol. 60
·期 10
·1595-1609
·
IF 3.046
Junfeng Ding,Tianran Wang,Zhixiong Chen,Zhiqiang Lin,Xuesi Chen,Chaoliang He
The efficiency of antitumor immunotherapy is usually limited by the immunosuppressive tumor microenvironment (TME). In this study, we developed a chemo-immunotherapy strategy that is able to improve the immunosuppressive TME for enhancing the antitumor efficacy. The chemo-immunotherapy was achieved by the topical co-delivery of a chemotherapeutic drug, Doxorubicin (DOX), an immune checkpoint blocking antibody targeting programmed cell death protein 1 (aPD-1), and an indoleamine-2,3-dioxygenase (IDO) inhibitor, 1-methyl- d -tryptophan ( d -1MT) by using a thermosensitive polypeptide hydrogel. It was revealed that the sustained DOX release from the hydrogel caused the immunogenic cell death (ICD) of B16F10 cells in vitro, and the tumor cell lysates subsequently promoted the activation of dendritic cells (DCs). After intratumoral injection into B16F10 melanoma-bearing mice, the DOX/aPD-1/D-1MT co-loaded hydrogel exhibited enhanced tumor inhibition efficacy and prolonged animal survival time, compared to the DOX/aPD-1/D-1MT mixed solution, DOX-loaded hydrogel or DOX/aPD-1 co-loaded hydrogel. The improvement of immunosuppressive TME and enhancement of antitumor immune response after the local chemo-immunotherapy were demonstrated by the augmented activation of DCs and increased infiltration of CD8 + and CD4 + T cells, as well as enhanced secretion of pro-inflammatory cytokines. Therefore, the hydrogel-based local chemo-immunotherapy system holds great potential for effective antitumor treatment. Graphical
研究领域:
肿瘤学
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生物材料
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免疫学
✓ 已验证
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2024
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IF 8.3
Xun Wang,Bin Yan,Hugang Li,Jianlan Yuan,Jingyi Guo,Siyao Wang,Penggao Dai,Xiaoli Liu
Indoleamine 2,3-dioxygenase (IDO), highly expressed in hepatocellular carcinoma (HCC), plays a pivotal role in creating an immune-suppressive tumor microenvironment. Inhibiting IDO activity has emerged as a promising immunotherapeutic strategy; however, the delivery of IDO inhibitors to the tumor site is constrained, limiting their therapeutic efficacy. In this study, we developed a magnetic vortex nanodelivery system for the targeted delivery of the IDO inhibitor NLG919, integrated with magnetic hyperthermia therapy to reverse the immune-suppressive microenvironment of liver cancer and inhibit tumor growth. This system comprises thermoresponsive polyethylenimine-coated ferrimagnetic vortex-domain iron oxide nanorings (PI-FVIOs) loaded with NLG919 (NLG919/PI-FVIOs). Under thermal effects, NLG919 can be precisely released from the delivery system, counteracting IDO-mediated immune suppression and synergizing with NLG919/PI-FVIOs-mediated magnetothermodynamic (MTD) therapy-induced immunogenic cell death (ICD), resulting in effective HCC suppression. In vivo studies demonstrate that this combination therapy significantly inhibits tumor growth and metastasis by enhancing the accumulation of cytotoxic T lymphocytes and suppressing regulatory T cells within the tumor. Overall, our findings reveal that NLG919/PI-FVIOs can induce a potent antitumor immune response by disrupting the IDO pathway and activating the ICD, offering a promising therapeutic avenue for HCC treatment.
研究领域:
癌症生物学
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纳米技术
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免疫疗法
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分子生物学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
·
2023
·
IF 17.4
Chen Xu,Keman Cheng,Xinwei Wang,Jingjing Liu,Jie Liang,Guangna Liu,Yichao Lu,Ming Tang,Dingfei Qian,Liting Chen,Zhenguo Cheng,Zhenning Wang,Xiao Zhao,Funan Liu
Through eliciting direct oncolysis, oncolytic viruses (OVs) induce release of tumor proteins, some of which can act as antigens to evoke an antitumor adaptive immune response. However, the poor immunogenicity and utilization efficiency of soluble tumor antigens limit the strength of the activated adaptive immune response and the clinical outcome of OVs. In this study, we found intratumoral injection of oncolytic virus, some of which was drained to the peritumoral lymph nodes. we proposed a strategy to modify oncolytic viruses (OVs) with antigen catchers (polyethylene glycol-linked maleimide) which efficiently capture tumor-derived proteins produced by oncolysis without diminishing its bioactivity of infecting tumor cells, then furtherly triggering enhanced antitumor adaptive immune response. In addition, the surface PEG layer protected AD 11 -Mal from the pre-exiting anti-AD 11 immunity to expand the applicability of AD 11 -Mal. Finally, we combined AD 11 -Mal with an indoleamine 2, 3-dioxygenase (IDO) inhibitor 1-methyl-tryptophan (1-MT) to overcome the local negative feedback in tumor immune microenvironment , which combinational regimen induced the long-lasting immune memory to inhibit tumor recurrence. In summary, our strategy greatly enhances the tumor antigen-specific adaptive immunity induced by OV therapy even in the presence of pre-exiting anti-OV immunity, which maybe promising for the development of next-generation OVs.
研究领域:
癌症免疫治疗
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分子生物学
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肿瘤学
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免疫学
✓ 已验证
DOI
高影响因子
BIOMATERIALS
·
2020
·
IF 10.317
Liangliang Dai,Xiang Li,Mengjiao Yao,Peiyun Niu,Xichen Yuan,Ke Li,Maowen Chen,Zengxiang Fu,Xianglong Duan,Haibin Liu,Kaiyong Cai,Hui Yang
IDO blockade-based immunotherapy has been impeded by the activation of antitumor immune response and low delivery efficiency of immunotherapeutic, resulting from natural biological barriers and immune resistance. Herein, a programmable drug delivery nanosystem with enhanced tumor penetration and endocytosis is constructed for chemotherapy-enhanced immunotherapy by loading immune checkpoint IDO inhibitor NLG919 in pH/redox cascade-responsive prodrug micelle . The nanosystem shrinked micelles sizes and converted charge from negative to positive for enhanced tumor penetration and endocytosis in responding to the weakly acidic tumor microenvironment . The endocytosed nanosystem dramatically disassembled and released curcumin and NLG919 in redox-rich cytoplasm. In vitro and in vivo studies demonstrate that the nanosystem not only effectively overcame biological barriers, but also significantly boosted antitumor immune response and reduced immune resistance. It was realized by the combined effects of chemotherapy-enhanced immunogenicity , and NLG919-induced IDO-blockade immunotherapy, consequently inhibiting tumor growth, metastasis and recurrence with high efficiency in vivo . The study offers a nanoplatform with deep tumor penetration, high cellular uptake and effective antitumor immune response for the advance of chemo-immunotherapy.
研究领域:
癌症治疗
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纳米技术
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药学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2020
·
IF 10.317
Qilin Li,Jia Liu,Huiling Fan,Lin Shi,Yan Deng,Lei Zhao,Mengxi Xiang,Yunruo Xu,Xulin Jiang,Guobin Wang,Lin Wang,Zheng Wang
Immunogenic chemotherapy (IC) is a type of chemotherapy where certain chemodrugs induce immunogenic cancer cell death (ICD), which in turn arouses T cell antitumor immunity. However, IC concurrently upregulates a key immune suppressor, indoleamine-2,3-dioxygenase (IDO), in both cancer cells and immune cells . IDO-mediated immunosuppression significantly offsets IC's therapeutic benefits in cancer patients , suggesting a necessity of combination with IDO inhibitors. Here, we report an enzyme-, pH-, and redox-triple-sensitive nanosystem using mesoporous silica nanoparticles (MSNs) as a core encapsulating doxorubicin (DOX, an immunogenic chemodrug); the core is coated with a shell ( β -CD-PEI/Ge1MT) for co-delivering 1-methyl-D-tryptophan (1 MT, an IDO inhibitor). By using these responsivenesses sequentially triggering the release of 1 MT into tumor extracellular compartment and DOX into intracellular endo/lysosomal compartment, this nanosystem ( [email protected] ) precisely delivers the drugs to their target cells residing in different compartments. Released 1 MT uptake by IDO-expressing dendritic cells (DCs) and cancer cells suppresses IDO activity, reducing immunosuppressive Tregs' presence; DOX unloaded within cancer cells induces ICD, promoting effector T-cell infiltration . In two preclinical cancer models, [email protected] potentiate both tumor local and systemic antitumor immunity, suppressing primary tumor growth by 78% with an 83% reduction in metastatic foci, as well as extending animal survival, thus strongly demonstrating [email protected] GMTMSNs' clinical translational potential.
研究领域:
癌症研究
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纳米技术
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免疫疗法
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2020
·
IF 3.701
Lvqi Zhou,Ning Hao,Xiaotian Li,Jiaxi Chen,Runyu Yang,Changqin Song,Yang Sun,Qi Zhang
In this study, we investigated the protective effect of Nattokinase (NK), the most active ingredient in natto used for healthcare, on dextran sulfate sodium (DSS)-induced chronic colitis and unraveled the potential mechanisms. NK dramatically attenuated clinical symptoms and pathological damage of DSS-induced chronic colitis. NK also inhibited proinflammatory cytokines production in DSS-induced colonic tissues. Mucosal integrity was maintained by NK. Moreover, nattokinase reversed DSS-induced decline of bacteria community diversity and intestinal microbial imbalance by decreasing levels of Firmicutes and increasing levels of Bacteroidetes . Tryptophan (Trp) metabolism analysis demonstrated that NK suppressed Trp catabolism especially the Kynurenine (Kyn) pathway in chronic colitis. Furthermore, NK strikingly down-regulated the protein expression of IDO-1 in chronic colitis mice. Taken together, the study demonstrated that NK relieved DSS-induced chronic colitis by regulating gut microbiota and suppressing Trp metabolism via inhibiting IDO-1. This study indicated that NK might be a promising and effective agent for IBD.
研究领域:
胃肠病学
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免疫学
·
微生物学
·
营养学
✓ 已验证
产品关联
DOI
高影响因子
Theranostics
·
2019
·
IF 8.063
Zeqian Huang,Gaofei Wei,Zishan Zeng,Yanjuan Huang,Liangfeng Huang,Yifeng Shen,Xiaoqi Sun,Congjun Xu,Chunshun Zhao
Cancer metastases is still a hurdle for good prognosis and live quality of breast cancer patients. Treatment strategies that can inhibit metastatic cancer while treating primary cancer are needed to improve the therapeutic effect of breast cancer. Methods: In this study, a dual functional drug conjugate comprised of protoporphyrin IX and NLG919, a potent indoleamine-2,3-dioxygenase (IDO) inhibitor, is designed to combine photodynamic therapy and immune checkpoint blockade to achieve both primary tumor and distant metastases inhibition. Liposomal delivery is applied to improve the biocompatibility and tumor accumulation of the drug conjugate (PpIX-NLG@Lipo). A series of in vitro and in vivo experiments were carried out to examine the PDT effect and IDO inhibition activity of PpIX-NLG@Lipo, and subsequently evaluate its anti-tumor capability in the bilateral 4T1 tumor-bearing mice. Results: The in vitro and in vivo experiments demonstrated that PpIX-NLG@Lipo possess strong ability of ROS generation to damage cancer cells directly through PDT. Meanwhile, PpIX-NLG@ Lipo can induce immunogenic cell death to elicit the host immune system. Furthermore, PpIX-NLG@Lipo interferes the activity of IDO, which can amplify PDT-induced immune responses, leading to an increasing amount of CD8 + T lymphocytes infiltrated into tumor site, finally achieve both primary and distant tumor inhibition. Conclusion: This work presents a novel conjugate approach to synergize photodynamic therapy and IDO blockade for enhanced cancer therapy through simultaneously inhibiting both primary and distant metastatic tumor.
研究领域:
肿瘤学
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药学
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免疫疗法
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Faisal Raza,Liangdi Jiang,Shulei Zhang,Hajra Zafar,Yujiao Qiu,Jing Su,Mingfeng Qiu
The efficient eradication of tumor cells remains a critical challenge in the realm of liver cancer therapies. The combination of chemotherapy and immunotherapy holds more significant potential for improving treatment efficacy. However, the effectiveness of immunotherapy is mainly impeded by the high activity of indoleamine 2,3-dioxygenase (IDO), which creates an immunosuppressive tumor microenvironment via robust proliferation of immunosuppressive T regulatory cells (T regs ) and inhibition of cytotoxic T lymphocytes (CTLs). Herein, we developed SR-ATO-ASIV@NS, a liver cancer-targeting peptide (SP94) modified RBCM-coated biomimetic nanosuspension. This innovative formulation incorporates the chemotherapeutic agent arsenic trioxide (ATO) and the immunomodulator astragaloside IV (AS-IV) as IDO inhibitor for the combined chemoimmunotherapy of liver cancer. The SR-ATO-ASIV@NS increased the solubility of both ATO and AS-IV and displayed excellent stability and exhibited high drug-loading efficiency, rendering it suitable for efficient dual drug delivery. Furthermore, this biomimetic nanosuspension efficiently evaded immune response and showed specific uptake in liver cancer cells via SP94 receptor-mediated endocytosis. The remarkable pharmacokinetic profile, characterized by prolonged blood circulation, enhanced the in vivo anti-tumor efficacy in H22 tumor bearing mice through the synergistic action of the dual drugs. On one hand, the released ATO resulted in excessive reactive oxygen species (ROS) generation, which stimulated the induction of apoptosis pathways via Bax/Bcl-2 and caspase mechanism. While on the other hand, AS-IV effectively blocked the IDO activity and hinders the production of T regs within the tumor microenvironment. Consequently, the reduced T regs population fosters the proliferation of CTLs, alleviating ITM and intensifying the immunotherapeutic response for the efficient killing of cancer cells. Additionally, the successful inhibition of liver cancer metastasis to the lungs and robust increase in T memory cells further boosted the anti-tumor therapeutic efficacy of SR-ATO-ASIV@NS. In summary, SR-ATO-ASIV@NS represents a novel and scientifically sophisticated strategy in targeted biomimetic nanotherapeutics. This approach not only enhances site-specific drug delivery but also showcases promising potential for advancing the field of combined chemoimmunotherapy for liver cancer.
研究领域:
癌症研究
·
药学
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纳米技术
·
免疫疗法
·
化疗
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
CHINESE JOURNAL OF CHEMISTRY
·
2024
·
IF 5.5
Junfeng Ding,Tianran Wang,Yan Rong,Chaoliang He,Xuesi Chen
Comprehensive Summary Due to the immunosuppressive tumor microenvironment (TME), T cells are usually inactivated and tend to differentiate into regulatory T cells (Tregs) in the tumor tissues, which seriously hinders the anti-tumor efficiency of immunotherapy. In this study, an immune-stimulating polypeptide hydrogel conjugated with an indoleamine-2,3-dioxygenase (IDO) inhibitor, 1-methyl- D -tryptophan (D1MT), through a glutathione (GSH)-responsive spacer was developed as an immunotherapy platform capable of regulating the TME. A combined immunotherapy system was further constructed through encapsulating doxorubicin (Dox) and immune checkpoint blocking antibody targeting programmed cell death protein 1 (aPD-1) in the hydrogel. Dox released from the hydrogel could cause the immunogenic cell death (ICD) of tumor cells and induce the maturation of antigen presenting cells (APCs). After intratumoral injection, the multiple agent-loaded hydrogel elicited effective anti-tumor immunity in mice bearing B16F10 melanoma. Moreover, compared with the control hydrogel without D1MT, the immune-stimulating hydrogel showed better efficiency in improving the immunosuppressive TME with increased number of activated T cells and reduced number of Tregs. Therefore, the immune-stimulating hydrogel has great potential as a stimuli-responsive platform for regulating suppressive TME and enhanced anti-tumor chemo-immunotherapy.
研究领域:
癌症免疫疗法
·
药学
·
生物医学工程
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免疫学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）