Journal of Advanced Research
·
2025
·
IF 13
Ruomeng Li,Xueyin Wu,Jing Yao,Jiawen Chen,Xindong Shui,Xiaoqing Zheng,Wujin Tian,Long Wang,Ying Zhou,Tao Zhang,Dongmei Chen,Yang Liu,Tae Ho Lee
Introduction The upregulation of death-associated protein kinase 1 (DAPK1) is involved in tau hyperphosphorylation, neuronal apoptosis and cognitive dysfunction, which are key pathological features of Alzheimer’s disease (AD). This result suggests that DAPK1 is novel therapeutic target for AD. Objectives This study aimed to evaluate the efficacy and mechanism of action of CJ1, a novel hydrophobic tagging (HyT)-based degrader, in targeting DAPK1 and alleviating in AD. Methods A library of HyT-based bifunctional molecules was synthesized and systematically screened for their ability to degrade DAPK1 in vitro . CJ1 emerged as the most potent candidate degrader of DAPK1, and its capacity to induce DAPK1 degradation via the proteasome system was further evaluated. Its effects on tau phosphorylation and neuronal viability were evaluated in multiple cellular models. The in vivo efficacy of systemic CJ1 administration was assessed in two tau-related pathology (tauopathy) mouse models, AAV-hTau-P301L and hTau transgenic mice. Behavioral, biochemical, and histological analyses were performed to evaluate cognitive function, tau pathology, neuroinflammation, neurodegeneration, and safety. Results CJ1 selectively promoted the posttranslational degradation of DAPK1 by the proteasome system without affecting DAPK1 mRNA expression. In vitro studies demonstrated that CJ1 significantly reduced tau phosphorylation at multiple AD-related sites. In vivo , CJ1 effectively penetrated the BBB, decreased the levels of both the soluble and insoluble forms of hyperphosphorylated tau, and suppressed the formation of neurofibrillary tangles. Additionally, CJ1 treatment restored synaptic and dendritic structures, enhanced spatial learning and memory, attenuated neuroinflammatory responses, preserved neuronal populations, and produced no evidence of systemic toxicity. Conclusion CJ1 functions as a potent and selective degrader of DAPK1, exerting neuroprotective effects by reducing tau hyperphosphorylation and preserving neuronal structural integrity. These findings support DAPK1 as a promising therapeutic target and suggest that further preclinical studies are warranted to evaluate CJ1 as a potential treatment for tauopathies associated with AD.
✓ 已验证
DOI
PubMed
高影响因子
Biomaterials Research
·
2025
·
IF 9.6
Anran Li,Cong Chen,Tongjia Zhang,Yuxin Tian,Yifan Cao,Xiaoming Zhao,Liping Wang
Human umbilical cord mesenchymal stem cell extracellular vesicles (hucMSC-EVs) exhibit remarkable potential for alleviating type 2 diabetes mellitus (T2DM). However, the role of hucMSC-EVs in T2DM, particularly concerning oxidative damage to pancreatic β cells, remains underexplored. This study utilized a high-fat diet and streptozotocin (STZ)-induced T2DM mouse model and an STZ-induced INS-1 cell damage model to investigate the effects and mechanisms of hucMSC-EVs. In the T2DM mouse model, hucMSC-EVs effectively lowered blood glucose levels, improved lipid metabolism disorders, and preserved liver function. Moreover, hucMSC-EVs enhanced insulin sensitivity and mitigated oxidative damage. Histological analysis confirmed that hucMSC-EVs marked alleviated liver, kidney, and pancreatic tissue damage. In vitro studies demonstrate that hucMSC-EVs enhance glucose absorption and glycogen synthesis in an insulin-resistant HepG2 model and stimulated insulin secretion in INS-1 cells under high-glucose conditions. In the STZ-induced INS-1 oxidative damage model, hucMSC-EVs protect against oxidative damage by increasing antioxidant enzyme activities, reducing reactive oxygen species production, and decreasing cell apoptosis. The effects were partially mediated by the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT and signal transducer and activator of transcription (STAT) signaling pathways, as well as the up-regulation of key antioxidant proteins such as Nrf2, SOD1, and Bcl2. Further research revealed that miR-191-5p, which is enriched in hucMSC-EVs, targets DAPK1 to activate the PI3K/AKT pathway, thereby contributing to the protective effects against oxidative damage. These findings highlight the critical role and underlying mechanisms of hucMSC-EVs in ameliorating metabolic dysfunction in T2DM, particularly the protective effects against oxidative damage, thus providing a novel strategy for the treatment of T2DM.
研究领域:
生物学
·
医学
·
细胞生物学
·
分子生物学
✓ 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
·1-15
·
IF 12.658
Cao Yi,Tu Yi,Xiong Jianbo,Tan Shengxing,Luo Lianghua,Wu Ahao,Shu Xufeng,Jie Zhigang,Li Zhengrong
Background Extracellular vesicles (EVs) derived from tumor-associated macrophages are implicated in the progression and metastasis of gastric cancer (GC) via the transfer of molecular cargo RNAs. We aimed to decipher the impact of microRNA (miR)-15b-5p transferred by M2 macrophage-derived EVs in the metastasis of GC.Methods Expression of miR-15b-5p was assessed and the downstream genes of miR-15b-5p were analyzed. GC cells were subjected to gain- and loss-of function experiments for miR-15b-5p, BRMS1, and DAPK1. M2 macrophage-derived EVs were extracted, identified, and subjected to co-culture with GC cells and their biological behaviors were analyzed. A lung metastasis model in nude mice was established to determine the effects of miR-15b-5p on tumor metastasis in vivo.Results miR-15b-5p was upregulated in GC tissues and cells as well as in M2 macrophage-derived EVs. miR-15b-5p promoted the proliferative and invasive potentials, and epithelial-mesenchymal transition (EMT) of GC cells. M2 macrophage-derived EVs could transfer miR-15b-5p into GC cells where it targeted BRMS1 by binding to its 3’UTR. BRMS1 was enriched in the DAPK1 promoter region and promoted its transcription, thereby arresting the proliferative and invasive potentials, and EMT of GC cells. In vivo experiments demonstrated that orthotopic implantation of miR-15b-5p overexpressing GC cells in nude mice displayed led to enhanced tumor metastasis by inhibiting the BRMS1/DAPK1 axis.Conclusion sOverall, miR-15b-5p delivered by M2 macrophage-derived EVs constitutes a molecular mechanism implicated in the metastasis of GC, and may thus be considered as a novel therapeutic target for its treatment.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR CELL
·
2024
·
IF 14.5
Zhenxi Zhang,Yanting Yang,Yang Chen,Jingyu Su,Wenjing Du
The functional integrity of CD8 + T cells is closely linked to metabolic reprogramming; therefore, understanding the metabolic basis of CD8 + T cell activation and antitumor immunity could provide insights into tumor immunotherapy. Here, we report that ME2 is critical for mouse CD8 + T cell activation and immune response against malignancy. ME2 deficiency suppresses CD8 + T cell activation and anti-tumor immune response in vitro and in vivo . Mechanistically, ME2 depletion blocks the TCA cycle flux, leading to the accumulation of fumarate. Fumarate directly binds to DAPK1 and inhibits its activity by competing with ATP for binding. Notably, pharmacological inhibition of DAPK1 abolishes the anti-tumor function conferred by ME2 to CD8 + T cells. Collectively, these findings demonstrate a role for ME2 in the regulation of CD8 + T cell metabolism and effector functions as well as an unexpected function for fumarate as a metabolic signal in the inhibition of DAPK1.
研究领域:
免疫学
·
肿瘤学
·
代谢生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOSENSORS & BIOELECTRONICS
·
2024
·
IF 10.7
Hong Tao,Shuyun Weng,Luyun Xu,Jianqing Ye,Min Fan,Yong Wang,Yao Lin,Duo Lin,Qingshui Wang,Shangyuan Feng
Long-stranded non-coding RNAs (lncRNA) have important roles in disease as transcriptional regulators, mRNA processing regulators and protein synthesis factors. However, traditional methods for detecting lncRNA are time-consuming and labor-intensive, and the functions of lncRNA are still being explored. Here, we present a surface enhanced Raman spectroscopy (SERS) based biosensor for the detection of lncRNA associated with liver cancer (LC) as well as in situ cellular imaging. Using the dual SERS probes, quantitative detection of lncRNA (DAPK1-215) can be achieved with an ultra-low detection limit of 952 aM by the target-triggered assembly of core–satellite nanostructures. And the reliability of this assay can be further improved with the R 2 value of 0.9923 by an internal standard probe that enables the signal dynamic calibration. Meanwhile, the high expression of DAPK1-215 mainly distributed in the cytoplasm was observed in LC cells compared with the normal ones using the SERS imaging method. Moreover, results of cellular function assays showed that DAPK1-215 promoted the migration and invasion of LC by significantly reducing the expression of the structural domain of death associated protein kinase. The development of this biosensor based on SERS can provide a sensitive and specific method for exploring the expression of lncRNA that would be a potential biomarker for the screening of LC.
研究领域:
纳米技术
·
癌症生物学
·
生物物理学
·
分子生物学
·
分析化学
✓ 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）