Advanced Healthcare Materials
·
2025
·
IF 9.6
Jie Zhao,Ming Li,Qiong Wu,Guanzhong Qiao,Hao Jiang,Sheng Zhao,Linhan Zhang,Song Wang,Huijie Jiang
Colorectal cancer (CRC) poses a significant therapeutic challenge due to its immunosuppressive tumor microenvironmentl (TME). In this environment, triggering receptors expressed on myeloid cells 2 (TREM2+) tumor-associated macrophages (TAMs) drive immune evasion and therapy resistance. In this study, CSF1R-IN-3@Mn@MPDA-antiTREM2 (CMMT) is presented, a manganese-doped mesoporous polydopamine nanoplatform conjugated with anti-TREM2 antibodies, which integrates TAM reprogramming and magnetic resonance imaging (MRI)-guided immune monitoring. CMMT has three key characteristics: 1) pH-responsive release of the Colony Stimulating Factor 1 Receptor (CSF1R) inhibitor CSF1R-IN-3 within acidic TME; 2) selective targeting of TREM2+ M2 macrophages, achieving 4.2-fold higher uptake compared to M1 subsets ( P < 0.001); and 3) dual modulation of TREM2 and CSF1R pathways, polarizing M2-TAMs toward pro-inflammatory M1 phenotypes. In orthotopic CRC models, CMMT synergizes with anti-PD-L1 therapy, reducing tumor volume by 72.5% compared to 42.1% for monotherapy ( P < 0.001). It also extends median survival from 28 to 52 days. Importantly, CMMT acts as an MRI contrast agent, with T1 signal intensity correlating with intratumoral TREM2+ macrophage density (r- 0.71, P < 0.05), enabling non-invasive assessment of TME remodeling. This theranostic platform bridges immune modulation and real-time monitoring, providing a promising strategy to overcome immunotherapy resistance in CRC.
研究领域:
肿瘤学
·
免疫学
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医学影像学
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产品关联
DOI
PubMed
高影响因子
Heliyon
·
2024
·
IF 3.4
Kai Wang,Shujie Zan,Jiachun Xu,Weiming Sun,Caixia Li,Wei Zhang,Daoyan Ni,Ruzhen Cheng,Lin Li,Zhen Yu,Linlin Zhang,Shuang Liu,Yuanwu Cui,Yulian Zhang
Background Aging is the primary risk factor for the onset of Alzheimer's disease (AD). Inflamma-aging is a major feature in the process of aging, and the chronic neuroinflammation caused by inflamma-aging is closely related to AD. As the main participant of neuroinflammation, the polarization of microglia (MG) could influence the development of neuroinflammation. Objective This study aims to observe the impact of YHD on microglia (MG) polarization and neuroinflammation to delay the onset and progression of AD. Methods In vivo experiment, four-month senescence accelerated mouse prone 8 (SAMP8) were used as the model group, the SAMR1 mice of the same age were used as the control group. In YHD group, 6.24 g/kg YHD was intragastrically administrated continuously for 12 weeks, and Ibuprofen 0.026 g/kg in positive control group. Morris Water Maze test was used to evaluate the learning and memory ability, Nissl's staining and immunofluorescence double staining for neuron damage and MG M1/M2 polarization, Enzyme-Linked Immunosorbent Assay (ELISA) for neuroinflammation biomarkers in hippocampus, Western blot for key protein expression of TREM2/NF-κB signaling pathway. In vitro experiments, 10 μM/l Aβ 1-42 induced BV-2 cell model was used to re-verify the effect of YHD regulating MG polarization to reduce neuroinflammation. Also, TREM2 small interfering RNA (siRNA) was used to clarify the key target of YHD. Results YHD could improve the learning and memory ability of SAMP8 mice evaluated by the Morris Water Maze test. Like Ibuprofen, YHD could regulate the M1/M2 polarization of MG and the levels of neuroinflammatory markers TNF-α and IL-10 in hippocampus, and relieve neuroinflammation and neuron loss. In addition, YHD could also regulate the expression of PU.1, TREM2, p–NF–κB P65 in the TREM2/NF-κB signaling pathway. Further in vitro experiments, we found that YHD had a significant regulatory effect on Aβ 1-42 -induced BV-2 cell polarization, and it could significantly increase PU.1, TREM2, decrease p–NF–κB P65, p -IKKβ, TNF-α, IL-6, IL-1β. At the same time, using siRNA to inhibit TREM2, it proved that TREM2 was a key target for YHD to promote Aβ 1-42 -induced BV-2 cell M2 polarization to reduce neuroinflammation. Conclusions YHD could regulate the TREM2/NF-κB signaling pathway through TREM2, thereby to adjust MG polarization and reduce AD-related neuroinflammation.
研究领域:
神经科学
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药理学
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中医药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2018
·Vol. 234
·期 2
·1880-1888
·
IF 3.923
Ying Ye,Yanan Song,Juhua Zhuang,Guoyu Wang,Jing Ni,Wei Xia
Echinacoside (ECH) is a phenylethanoid glycoside extracted from a Chinese herbal medicine, Cistanches salsa . ECH possesses many biological properties, including anti-inflammation, neural protection, liver protection, and antitumor. In the current study, we aimed to explore the effects of ECH on hepatocellular carcinoma (HCC) and the underlying mechanisms. The results showed that ECH could attenuate diethylnitrosamine (DEN)-induced HCC in mice, and exerted antiproliferative and proapoptotic functions on HepG2 HCC cell line. ECH exposure in HepG2 cells dose-dependently reduced the phosphorylation of AKT (p-AKT) and enhanced the expression of p21 (a cell cycle inhibitor) and Bax (a proapoptotic protein). Furthermore, ECH significantly suppressed insulin-like growth factor-1-induced p-AKT and cell proliferation. These data indicated that phosphoinositide 3-kinase (PI3K)/AKT signaling was involved in the anti-HCC activity of ECH. Gene set enrichment analysis results revealed a positive correlation between the PI3K pathway and triggering receptors expressed on myeloid cells 2 (TREM2) expression in HCC tissues. ECH exposure significantly decreased TREM2 protein levels in HepG2 cells and DEN-induced HCC. Furthermore, ECH-mediated proliferation inhibition and AKT signaling inactivation were notably attenuated by TREM2 overexpression. In conclusion, ECH exerted its antitumor activity via decreasing TREM2 expression and PI3K/AKT signaling.
研究领域:
肿瘤学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2025
·Vol. 14
·期 12
·1495
·
IF 6.6
Tiantian Zhang,Shuangxi Zhang,Jiayang Ma,Dmitrii Atiakshin,Shujun Han,Mami Noda,Midori Hiramatsu,Jiankang Liu,Yunhua Peng,Jiangang Long
Neuroinflammation driven by microglial activation is a hallmark of Alzheimer’s disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial inflammation, yet strategies to modulate its expression remain limited. Safflower leaves, a vegetable rich in flavonoids—particularly luteolin—were previously shown to attenuate neuroinflammation, reduce oxidative stress, and ameliorate cognitive impairment in APP/PS1 mice. Here, we demonstrated that safflower leaves inhibit microglial inflammation and upregulate TREM2 in APP/PS1 mice. Luteolin, the major active flavonoid in safflower leaves, exerted anti-inflammatory effects in lipopolysaccharides (LPS)-activated microglia. Mechanistically, luteolin enhancedTrem2transcription by activating forkhead box protein O3 (FOXO3), a novel transcriptional regulator ofTrem2identified through promoter analysis. FOXO3 binding to theTrem2promoter was essential for this regulation, and luteolin further promoted FOXO3 nuclear translocation. Crucially,Trem2knockdown attenuated luteolin’s anti-inflammatory effects, confirming TREM2 as a key mediator. Overall, our study reveals the FOXO3-TREM2 axis as a potential therapeutic target for neuroinflammation and highlights luteolin present in safflower leaves as a candidate dietary intervention for AD, providing new mechanistic insights into the anti-inflammatory activity of this natural antioxidant.
研究领域:
神经科学
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分子生物学
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免疫学
·
营养科学
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药理学
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产品关联
DOI
PubMed
高影响因子
CELL
·
2026
·Vol. 189
·期 3
·853-871
·
IF 42.5
Xinyan Li,Xiaomei Tang,Jinyu Zeng,Limin Duan,Zhenye Hou,Lanfang Li,Yiqing Guo,Changdong Chai,Jiahao Liu,Ya Wang,Ling-Qiang Zhu,Hao Li,Tongmei Zhang,Yue Wang,Aodi He,Youming Lu
Alzheimer’s disease (AD) and cancer are among the most devastating diseases worldwide. Epidemiological data indicate that the incidence of AD significantly decreases in patients with a history of cancer. However, whether and how peripheral cancer may affect AD progression is yet to be studied. Here, we find that peripheral cancer inhibits amyloid pathology and rescues cognition via secretion of cystatin-c (Cyst-C), which binds amyloid oligomers and activates triggering receptor expressed on myeloid cells 2 (TREM2) in microglia, enabling microglia to degrade the pre-existing amyloid plaques in AD mice. These effects of Cyst-C are abolished by a cell-type-specific deletion ( Cx3cr1 TREM2−/− ) or mutation of TREM2 (TREM2 R47H ) or Cyst-C (Cyst-C L68Q ) in microglia. Together, these findings provide significant conceptual advances into cancer neuroscience and establish therapeutic avenues that are distinct from the present amyloid-lowering strategies, aiming at degrading the existing amyloid plaques for precision-targeted AD therapy.
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 8.3
Yingying Xie,Haoming He,Yike Li,Qiang Chen,Sunjing Fu,Zhe Wang,Gaiyan Feng,Yanping Li,YanXiang Gao,Jingang Zheng
Background Heart failure with preserved ejection fraction (HFpEF) constitutes over 50% of heart failure cases but lacks disease-modifying therapies. The pathophysiological role of eicosapentaenoic acid (EPA) in HFpEF remains undefined. Methods Integrated lipidomics was conducted across HFpEF discovery and validation cohorts. "Two-hit" murine HFpEF model combining high-fat diet (HFD) and 0.5g/L L-NAMEwas established to recapitulate human metabolic-inflammatory pathology. EPA’s efficacy was evaluated through prophylactic/therapeutic interventions (160/320 mg/kg/day, human-equivalent 2/4 g/day). Mechanistic studies integrated transcriptomics, molecular docking, triggering receptor expressed on myeloid cells 2 (TREM2) knockout, and siRNA silencing. Results Plasma EPA deficiency correlated with diastolic dysfunction severity and conferred incremental diagnostic value. High-dose EPA (4 g/day equivalent) prevented/reversed diastolic impairment and apoptosis in HFpEF mice. EPA rescued impaired efferocytosis through dual modulation of TREM2, concurrently enhancing functional transmembrane receptor expression while suppressing pathological ectodomain shedding. TREM2 ablation attenuated EPA-mediated benefits on diastolic function and efferocytosis. Conclusion Our work identifies plasma EPA depletion as a potential biomarker for risk stratification and delineates the EPA-TREM2-efferocytosis axis as a putative therapeutic mechanism for HFpEF, suggesting the potential of EPA as a theranostic candidate.
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DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2025
·Vol. 63
·期 1
·215
·
IF 4.3
Wanyi Fang,Shanshan Liu,Yifei Wu,Ting Chen,Xiaohe Lu,Hui Chen
Diabetic retinopathy (DR) is a common neurovascular complication of diabetes and a leading cause of vision loss in the advanced stages. Identifying therapeutic targets to prevent early progression of DR is critical for preserving visual function. Interleukin-12 (IL-12) has emerged as a potential therapeutic agent for early-stage diabetic retinal neurodegeneration. In this study, diabetic mouse models were established, followed by intravitreal injection of IL-12 to evaluate its effects using hematoxylin and eosin staining and RNA sequencing. IL-12 treatment partially prevented the thinning of the nerve fiber layer, ganglion cell layer, and total retina. Bioinformatics analysis of RNA sequencing data revealed enrichment of microglial signatures and enhanced phagocytic function. Western blotting analysis showed that IL-12 promoted the phosphorylation of signal transducer and activator of transcription 4 (STAT4) in microglia. Bioinformatics and quantitative reverse transcription polymerase chain reaction analyses demonstrated that STAT4 activation upregulated the transcription of phagocytosis-related genes, including triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12). In vitro and in vivo experiments confirmed that IL-12 upregulates the TREM2/DAP12 signaling pathway on the microglial membrane, enhancing microglial proliferation and phagocytic activity under high-glucose conditions. These findings indicated that IL-12 mitigates early neural injury in DR by promoting microglial phagocytosis through the upregulation of TREM2/DAP12.
研究领域:
眼科学
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神经科学
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免疫学
·
分子生物学
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糖尿病研究
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL BRAIN RESEARCH
·
2021
·Vol. 239
·期 11
·3315-3325
·
IF 1.972
Yu Tao,Fu Hui,Sun Jing-Jing,Ding Dan-Rui,Wang Hua
To investigate the association of miR-106b-5p with neuroinflammation and microglial activation in a status epilepticus (SE) mouse model. We examined changes in the expression of microRNA-106b-5p (miRNA-106b-5p), repulsive guidance molecule A (RGMa), triggering receptor expressed on myeloid cells 2 (TREM2), and the microglia-related markers interleukin (IL)-1β, IL-4, IL-6, IL-10, inducible nitric oxide synthase (iNOS), and arginase-1 (Arg-1) in the mouse hippocampus of the lithium–pilocarpine-induced SE mouse model. Eighty-four female C57BL/6 mice were randomly divided into a normal control group ( n = 12), and six SE groups ( n = 12/group), which were monitored at 6 h and at 1, 3, 7, 14, and 21 days (d) post-SE induction. Unlike in the dentate gyrus, immunohistochemical staining revealed prominent neuronal swelling at 6 h, significant neuronal loss and apoptosis on day 3, and recovery by day 14 in the hippocampal cornu ammonis (CA)1 and CA3 pyramidal cells in SE mice. We noted elevated levels of miRNA-106b-5p and all microglia-related markers, which peaked at 3 days post-SE, except IL-4, which peaked at 7 days post-SE, indicating inflammation and microglial activation. RGMa and TREM2 levels decreased at 6 h post-SE. All markers but miRNA-106b-5p, RGMa, and TREM2 returned to baseline levels at 21 days post-SE. Dual luciferase reporter gene assay showed that microRNA-106b-5p can interact with RGMa. We observed that miR-106b-5p level increased while both RGMa and TREM2 levels decreased post-SE and showed associations with microglial activation and inflammation in the mouse hippocampus, suggesting their potential as SE therapeutic targets.
研究领域:
神经科学
·
分子生物学
·
神经炎症
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小胶质细胞
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癫痫
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2025
·
IF 5.4
Yaojun Ju,Yichen Yan,Xinhui Wang,Shan Li,Jialei Wang,Zixiao Wang,Yuling Dong,Junping Wang
This study investigated the therapeutic potential and mechanisms of Acer truncatum Bunge seeds oil (ATSO) against cuprizone-induced white matter injury and cognitive decline. A comprehensive analysis integrating techniques from animal behavior, histopathology, immunology and network pharmacology was performed. The results showed that ATSO ameliorated the cuprizone-induced cognitive impairment, corpus callosum demyelination, synaptic loss, and inflammatory activation of microglia and astrocytes. Mechanistically, ATSO reversed the cuprizone-induced demyelination by enhancing sphingomyelin metabolism and activating TREM2-APOE signaling pathway. The network pharmacology study revealed that the cognitive protection, sphingomyelin metabolism regulation, and anti-inflammatory effects of ATSO were mediated by its unsaturated fatty acids components. Validated by experimental data, the core targets of ATSO were found to center on the TREM2 network. In conclusion, ATSO ameliorates cuprizone-induced cognitive impairment and brain white matter lesions by improving sphingomyelin metabolism and alleviating neuroinflammation through activation of TREM2 signaling pathway.
研究领域:
神经科学
·
药理学
·
营养生物化学
·
神经免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）