American Journal of Translational Research
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2016
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IF 3.146
Ke Li,Xia Gong,Ge Kuang,Rong Jiang,Jingyuan Wan,Bin Wang
Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury with high morbidity and mortality due to limited therapy. Here, we examine whether sesamin attenuates renal IRI in an animal model and explore the underlying mechanisms. Male mice were subjected to right renal ischemia for 30 min followed by reperfusion for 24 h with sesamin (100 mg/kg) during which the left kidney was removed. Renal damage and function were assessed subsequently. The results showed that sesamin reduced kidney ischemia reperfusion injury, as assessed by decreased serum creatinine (Scr) and Blood urea nitrogen (BUN), alleviated tubular damage and apoptosis. In addition, sesamin inhibited neutrophils infiltration and pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β production in IR-preformed kidney. Notably, sesamin promoted the expression of CD39, A2A adenosine receptor (A2AAR), and A2BAR mRNA and protein as well as adenosine production. Furthermore, CD39 inhibitor or A2AR antagonist abolished partly the protection of sesamin in kidney IRI. In conclusion, sesamin could effectively protect kidney from IRI by inhibiting inflammatory responses, which might be associated with promoting the adenosine-CD39-A2AR signaling pathway.
研究领域:
药理学
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肾病学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2025
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IF 14.6
Yuanyuan Zhang,Weiwei Jin,Zhichao Deng,Bowen Gao,Yuanyuan Zhu,Junlong Fu,Chenxi Xu,Wenlong Wang,Ting Bai,Lianying Jiao,Hao Wu,Mingxin Zhang,Mingzhen Zhang
Sonodynamic therapy (SDT) can potentially induce immunogenic cell death in tumor cells, leading to the release of ATP, and facilitating the initiation of an immune response. Nevertheless, the enzymes CD39 and CD73 can swiftly convert ATP into immunosuppressive adenosine (ADO), resulting in an immunosuppressive tumor microenvironment (TME). This study introduced a nanomedicine (QD/POM1@NP@M) engineered to reprogram TME by modulating the CD39/CD73/ADO pathway. The nanomedicine encapsulated sonosensitizers silver sulfide quantum dots, and the CD39 inhibitor POM1, while also incorporating homologous tumor cell membranes to enhance targeting capabilities. This integrated approach, on the one hand, stimulates the release of ATP via SDT, thereby initiating the immune response. In addition, it reduced the accumulation of ADO by inhibiting CD39 activity, which ameliorated the immunosuppressive TME. Upon administration, the nanomedicine demonstrated substantial anti-tumor efficacy by facilitating the infiltration of anti-tumor immune cells, while reducing the immunosuppressive cells. This modulation effectively transformed the TME from an immunologically “cold” state to a “hot” state. Furthermore, combined with the checkpoint inhibitor α -PDL1, the nanomedicine augmented systemic anti-tumor immunity and promoted the establishment of long-term immune memory. This study provides an innovative strategy for combining non-invasive SDT and ATP-driven immunotherapy, offering new ideas for future cancer treatment.
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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产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
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2024
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IF 4.6
Xiong Zhonghua,Deng Jiahui,Xie Pandeng,Tang Chongyang,Wang Jing,Deng Qinqin,Yang Yujiao,Zhang Jing,Guo Mengyi,Wang Xiongfei,Guan Yuguang,Luan Guoming,Zhou Jian,Li Tianfu
Deep brain stimulation (DBS) of the anterior nucleus of the thalamus is an efficacious treatment option for patients with refractory epilepsy. Our previous study demonstrates that adenosine is a potential target of DBS for the treatment of epilepsy. Equilibrative nucleoside transporters-1 (ENT1) and ectonucleotidases (CD39, CD73) function as regulators of extracellular adenosine in the brain. It is unclear whether ENT1, CD39, and CD73 are involved in the mechanism of DBS for epilepsy. A total of 48 SD male rats were divided into four groups: control (naïve rats), Pilo (pilocarpine induced rats with epilepsy), DBS (rats with epilepsy treated with DBS for 8 weeks), and sham. In the present study, video electroencephalogram monitoring, Morris water maze assays, in vivo measurements of adenosine using fiber photometry, histochemistry, and western blot were performed on the hippocampus. DBS markedly attenuated spontaneous recurrent seizures (SRSs) and enhanced spatial learning in rats with epilepsy, assessed through video-EEG and water maze assays. Fibred photometry measurements of an adenosine sensor revealed dynamic increase in extracellular adenosine during DBS. The expressions of ENT1, CD39, and CD73 in Pilo group and sham group increased compared with the control group, while the expressions of ENT1, CD39, and CD73 in DBS group decreased compared to that of Pilo group and sham group. The findings indicate that DBS reduces the number of SRSs and improves spatial memory in rats with epilepsy with concomitant decrease of ENT1, CD39, and CD73 expressions. Adenosine-modulating enzymes might be the potential targets of DBS for the treatment of epilepsy.
研究领域:
神经科学
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药理学
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癫痫学
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神经病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2026
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IF 11.5
Chunlian Ye,Yun Zheng,Huilan He,Jinlong Ji,Liang Liu,Yu Sun,Yuwei Peng,Shenqiang Wang,Ying Zhang,Zhiyuan Zhong
The efficacy of radio-immunotherapy is generally limited by adaptive resistance mechanisms that create an immunosuppressive tumor microenvironment. The molecular drivers of this radio-resistance remain poorly defined. Here we identify the ectonucleotidase CD39 as a critical driver of radiotherapy (RT)-induced immunosuppression. We show that RT robustly upregulates CD39 on tumor cells and tumor-infiltrating immune cells, creating an adenosine-rich tumor microenvironment that promotes immune evasion. Pharmacological inhibition of CD39 with POM-1 reverses this immunosuppression, synergizing with RT to enhance anti-tumor immunity. Furthermore, we engineer an immuno-gel (POM-1@iGel) for sustained local CD39 inhibition and concurrent immune stimulation. A single intratumoral injection of POM-1@iGel in combination with single-fraction RT establishes durable systemic anti-tumor immunity with immunological memory and leads to complete tumor regression in a murine colorectal cancer model. These findings elucidate a critical mechanism of RT-induced immune escape and present a rational, scalable strategy to overcome RT-induced immunosuppression and boost radio-immunotherapy in solid tumors.
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Tingting Wu,Lulu Wang,Chen Jian,Chen Gao,Yajing Liu,Zhiwen Fu,Chen Shi
Refractory fracture presents an intractable challenge in trauma treatment. Selective polarization of macrophages as well as the recruitment of osteogenic precursor cells play key roles in osteogenic differentiation during fracture healing. Here we constructed regulatory T cell (Treg)-derived exosomes (Treg-Exo) for the treatment of fracture. The obtained exosomes displayed a spheroid shape with a hydrated particle size of approximately 130 nm. With further purification using CD39 and CD73 antibody-modified microfluidic chips, CD39 and CD73 specifically expressing exosomes were obtained. This kind of Treg-Exo utilized the ectonucleotidases of CD39 and CD73 to catalyze the high level of ATP in the fracture area into adenosine. The generated adenosine further promoted the selective polarization of macrophages. When interacting with mesenchymal stem cells (MSCs, osteogenic precursor cells), both Treg-Exo and Treg-Exo primed macrophages facilitated the proliferation and differentiation of MSCs. After administration in vivo , Treg-Exo effectively promoted fracture healing compared with conventional T cell-derived exosome. To further improve the delivery efficacy of exosomes and integrate multiple biological processes of fracture healing, an injectable hydrogel was fabricated to co-deliver Treg-Exo and stromal cell-derived factor 1 alpha (SDF-1α). With the dual effect of Treg-Exo for macrophage polarization and SDF-1α for MSC recruitment, the multifunctional hydrogel exerted a synergistic effect on fracture repair acceleration. This study provided a promising therapeutic candidate and synergistic strategy for the clinical treatment of fracture.
研究领域:
免疫学
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再生医学
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骨科
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF IMMUNOLOGY
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2024
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IF 3.6
Wang Li,Cao Limin,Li Zhihong,Shao Zhugui,Chen Xia,Huang Zhicheng,He Xiaoxiao,Zheng Junke,Liu Li,Jia Xin-Ming,Xiao Hui
The cyclic GMP-AMP synthase (cGAS)–stimulator of IFN genes (STING) pathway is instrumental to antitumor immunity, yet the underlying molecular and cellular mechanisms are complex and still unfolding. A new paradigm suggests that cancer cells’ cGAS-synthesized cGAMP can be transferred to tumor-infiltrating immune cells, eliciting STING-dependent IFN-β response for antitumor immunity. Nevertheless, how the tumor microenvironment may shape this process remains unclear. In this study, we found that extracellular ATP, an immune regulatory molecule widely present in the tumor microenvironment, can potentiate cGAMP transfer, thereby boosting the STING signaling and IFN-β response in murine macrophages and fibroblasts. Notably, genetic ablation or chemical inhibition of murine volume-regulation anion channel LRRC8/volume-regulated anion channel (VRAC), a recently identified cGAMP transporter, abolished ATP-potentiated cGAMP transfer and STING-dependent IFN-β response, revealing a crucial role of LRRC8/VRAC in the cross-talk of extracellular ATP and cGAMP. Mechanistically, ATP activation of the P2X family receptors triggered Ca2+ influx and K+ efflux, promoting reactive oxygen species production. Moreover, ATP-evoked K+ efflux alleviated the phosphorylation of VRAC’s obligate subunit LRRC8A/SWELL1 on S174. Mutagenesis studies indicated that the phosphorylation of S174 on LRRC8A could act as a checkpoint for VRAC in the steady state and a rheostat of ATP responsiveness. In an MC38-transplanted tumor model, systemically blocking CD39 and ENPP1, hydroxylases of extracellular ATP and cGAMP, respectively, elevated antitumor NK, NKT, and CD8+ T cell responses and restrained tumor growth in mice. Altogether, this study establishes a crucial role of ATP in facilitating LRRC8/VRAC transport cGAMP in the tumor microenvironment and provides new insight into harnessing cGAMP transfer for antitumor immunity.
研究领域:
免疫学
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癌症生物学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
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2025
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IF 14.1
Hongrui Fan,Hongyi Chen,Haolin Song,Chufeng Li,Yu Wang,Zhenhao Zhao,Qin Guo,Xuwen Li,Mingxuan Liu,Tao Sun,Chen Jiang
KRAS mutations are find in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases, making PDAC exhibit intrinsic resistance to chemotherapy and reshape the immunosuppressive tumor microenvironment (TME), disappointing the clinically preferred chemotherapy-immunotherapy combination. Standing on the cross point of therapeutic resistance, the aberrant adenosine metabolism contributes greatly to chemo- and immunotherapy tolerance. KRAS mutation-induced over-expression of key enzyme CD39 is believed to be involved in shaping the immunosuppressive TME, as it catalyzes the hydrolysis of extracellular ATP into immunosuppressive adenosine. Meanwhile, the loss of equilibrative nucleoside transporters (ENTs) leads to the accumulation of adenosine and the intracellular delivery difficulty of gemcitabine, further vanishing patients’ hope of benefiting from either chemotherapy or immunotherapy. The key challenge is to modulate the aberrant metabolism, also enhance gemcitabine intracellular delivery. Therefore, ROS-responsive positively-charged polymer B-PDEA is prepared and assembled into polyplexes for loading CD39-down-regulating small interfering RNA. Gemcitabine-loaded albumin is coupled with the polyplexes through enzyme-cleavable peptide, forming the intact nanoparticles for the co-delivery of the first-line chemotherapeutic drug and CD39-regulating nucleic acid, showing enhanced gemcitabine intracellular delivery and adenosine metabolism regulating capacity. This approach activated antitumor immunity while achieving chemosensitization by changing the metabolic-immune crosstalk of TME, showcasing great potential for PDAC treatment.
研究领域:
纳米医学
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肿瘤学
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药剂学
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分子生物学
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免疫治疗
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药物递送
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Chaonan Shi,Minglong Chen,Xiaodie Li,Yanping Fu,Dan Yang,Ting Wen,Wanchen Zhao,Ying Sun,Wenhao Wang,Chao Lu,Qiaoli Wu,Chuanbin Wu,Xin Pan,Guilan Quan
Immunogenic cell death (ICD) is associated with the release of damage-associated molecular patterns, including ATP, to promote an effective immune cycle against tumors. However, tumors have evolved an effective strategy for degrading extracellular immunostimulatory ATP via the ATP-adenosine axis, allowing the sequential action of the ectonucleotidases CD39 to degrade accumulated immunostimulatory ATP into pleiotropic immunosuppressive adenosine. Here, an ingenious dissolving microneedle patch (DMNs) is designed for the intralesional delivery of CD39 inhibitor (sodium polyoxotungstate, POM-1) and ICD inducer (IR780) co-encapsulated solid lipid nanoparticles (P/I SLNs) for antitumor therapy. Upon insertion into the tumor site, IR780 induces ICD modalities with the release of damage-associated molecular patterns from endogenous tissues, which activates the antitumor immune cycle. Simultaneously, POM-1 promotes the liberation of immunostimulatory ATP and lowers the level of immunosuppressive extracellular adenosine, which supported immune control of tumors via recruiting CD39-expressing immune cells. In vivo antitumor studies prove that this platform can effectively eliminate mice melanoma (tumor growth inhibitory rate of 96.5%) and colorectal adenocarcinoma (tumor growth inhibitory rate of 93.5%). Our results shed light on the immunological aspects of combinatorial phototherapy and ATP-adenosine regulation, which will broaden the scope of synergistic antitumor immunotherapy .
研究领域:
癌症免疫疗法
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药学
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生物医学工程
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分子生物学
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产品关联
DOI
PubMed
高影响因子
iScience
·
2024
·
IF 4.6
Junyang Li,Bingjie Mei,Lu Feng,Xiaoxin Wang,Dengfeng Wang,Jianming Huang,Guonan Zhang
Reprogramming tryptophan metabolism (TRP) may be able to overcome immunosuppression and restore the immune checkpoint blockade (ICB) response in epithelial ovarian cancer (EOC) patients resistant to ICB therapy. Because TRP metabolism is involved in the kynurenine/indole and serotonin pathways of tryptophan metabolism. Herein, employing amitriptyline (AMI), an antagonist of TLR4 and serotonin transporter (SERT), we revealed that AMI remodels the immunological landscape of EOC. In particular, AMI lowered the expression of IDO1, IL-4I1 and PD-L1, the quantity of KYN and indoles, and the level of immunosuppressive immune cells MDSC, Tregs and CD8+CD39+/PD-1+ T cell. AMI boosted the killing potential of anti-PD-1-directed CD8+T cells and worked in concert with PD-1 inhibitor to suppress tumor growth and to prolong the survival of EOC-bearing mice. This work highlights AMI as an effective regulator of ICB response by manipulating EOC cell TRP metabolism, indicating it could be a potential strategy for improving EOC ICB therapy.
研究领域:
肿瘤学
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免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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