COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2025
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IF 5.4
Junling An,Hao Li,Wenjing Wen,Gaojian Liu,Zixuan Huang,Xinwei Zhao,Gaofeng Liang
Liver cancer, particularly hepatocellular carcinoma (HCC), presents significant therapeutic challenges due to factors such as drug resistance and systemic toxicity. Ferroptosis, an iron-dependent form of cell death, offers a promising alternative to overcome these challenges. This study investigates the use of folic acid-modified iron oxide nanoparticles as a delivery system for miR-214-3p to promote ferroptosis in liver cancer cells. The folic acid modification enhances the efficiency of nanoparticle-mediated miR-214-3p delivery, thereby improving its therapeutic potential. miR-214-3p plays a dual role in promoting ferroptosis: first, by downregulating lipocalin-2 (LCN2), it acts synergistically with iron oxide nanoparticles to increase intracellular iron levels, reduce iron excretion, and promotes the Fenton reaction; second, by inhibiting glutathione peroxidase 4 (GPX4), it weakens cellular antioxidant defenses, further promoting ferroptosis. Our in vitro experiments demonstrated that the folic acid-modified nanoparticles effectively delivered miR-214-3p, resulting in significant ferroptosis in liver cancer cells. Animal models showed that FeNP/miR could effectively target tumors and had excellent tumor suppressive effects. This research highlights a promising approach for targeting HCC through enhanced nanoparticle-based gene therapy, offering a potential strategy in cancer treatment.
研究领域:
肿瘤学
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分子生物学
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纳米医学
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DOI
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Renmin Xiao,Jingmei Pan,Mengyi Yang,Hua Liu,Aohan Zhang,Xing Guo,Shaobing Zhou
Astrocytes can be reacted to “reactive astrocytes” after ischemia-reperfusion injury, in which A1 phenotype causes neuronal and oligodendrocyte death, whereas the A2 phenotype exerts neuroprotective effects, thus regulating reactive astrocyte to A2 type is a potential target for stroke therapy. Lcn2 level is highly associated with the phenotypic polarization of astrocytes. We found that silencing the Lcn2 gene by adeno-associated virus (AAV)-Lcn2 shRNA adenovirus resulted in a dramatic decrease in A1-type astrocytes and increase in A2 astrocytes in MCAO mice. Hence, a nanoplatform was developed for stroke therapy by inhibiting Lcn2. This system was fabricated by N-acetyl Pro-Gly-Pro peptide-decorated rod-shaped poly (lactic-co-glycolic acid) nanoparticles loading with rolipram (AP@R). The nanodrug can be efficiently taken up by neutrophils simultaneously through morphology-mediated passive targeting and Cxcr2 receptor-mediated active targeting, subsequently crossing the blood-brain barrier (BBB) by hitchhiking neutrophils. When accumulating at the brain parenchyma, the released rolipram can inhibit the Lcn2 level, thereby reversing the astrocyte phenotype to alleviate neuroinflammation and promote BBB repair. This work provides a new strategy for treating ischemic stroke.
研究领域:
神经科学
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分子生物学
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药理学
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治疗学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Wei Yang,Xihan Che,Rui Ding,Lina Shang,Yujun Yuan,Ning Li,Yu Li
UBA6 is down-regulated in the brain tissues of CLP mice. • UBA6 overexpression mitigates neuroinflammation in the CLP mice. • UBA6 overexpression alleviates the behavioral abnormalities of CLP mice. • UBA6 mediates the ubiquitination and degradation of LCN2. • UBA6 regulates LPS-induced microglial inflammation through LCN2. Sepsis-associated encephalopathy (SAE) is a common secondary complication of sepsis, accompanied by neuroinflammation and neuronal apoptosis. As an E1 ubiquitin-activating enzyme, ubiquitin-like modifier-activating enzyme 6 (UBA6) deficiency aggravates inflammation. Herein, we first confirmed that UBA6 is decreased in brain tissues of cecal ligation and puncture (CLP)-induced SAE mice. Lentivirus was bilaterally injected into the hippocampus to establish in vivo UBA6 overexpression. Lentivirus-mediated overexpression of UBA6 effectively inhibited microglial activation, downregulated the levels of pro-inflammatory mediators, and reduced inflammatory cytokine release. Furthermore, UBA6 upregulation mitigated neuronal apoptosis and improved spatial learning and memory functions in SAE model mice. For in vitro validation, BV-2 microglial cells were stimulated with 100 ng/mL LPS for 24 h. Consistent with in vivo observations, exogenous UBA6 decreased the proportion of CD86-positive pro-inflammatory microglia. After culturing HT-22 neuronal cells with BV-2 cell conditioned medium, UBA6 overexpression elevated neuronal viability and restrained caspase-3-mediated neuronal apoptosis. Quantitative proteomics was applied to screen and identify lipocalin 2 (LCN2) as a downstream interacting partner of UBA6. Mechanistically, UBA6 binds LCN2 at residue 147 to accelerate K48 ubiquitination and degradation of LCN2, which attenuates neuronal apoptosis induced by LCN2 paracrine. Rescue assays revealed that ectopic LCN2 expression reversed the protective effects of UBA6 against neuroinflammation and neuronal apoptosis. In summary, UBA6 ameliorates SAE-induced cerebral damage, neuroinflammation and cognitive dysfunction via accelerating LCN2 ubiquitination and degradation. These findings advance the mechanistic understanding of SAE progression and establish UBA6/LCN2 as a prospective therapeutic target for SAE intervention. Download: Download high-res image (131KB) Download: Download full-size image
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DOI
高影响因子
Advanced Science
·
2026
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IF 14.1
Zimei Wu,Yan Xu,Lang Qin,Zemin Ling,Yingjie Mai,Xiong Tian Guo,Jiajia Chen,Leping Yan,Lin Wang,Liming Bian,Fuxin Wei
Intervertebral disc degeneration (IVDD) is driven by persistent inflammation–oxidative stress that disrupts annulus fibrosus (AF) homeostasis. Guided by network pharmacology and docking, we prioritized the NF-κB–LCN2 axis as a druggable target of wedelolactone (WDL). To achieve targeted modulation, we engineered a dual-network ROS-responsive hydrogel (WPG) in which a phenylboronic-ester/PVA redox-cleavable network interpenetrates a covalently crosslinked GelMA–elastin matrix, enabling mechanically robust yet stimulus-triggered WDL release. WDL suppressed NF-κB activation and downregulated LCN2 in both macrophages and AF cells. Conditioned-medium co-culture demonstrated that WDL disrupts macrophage-derived LCN2-mediated paracrine amplification, breaking the self-sustaining inflammatory loop. Bulk RNA-seq across both cell types revealed coordinated downregulation of NF-κB – driven chemokine cascades and restoration of adhesion and ECM gene programs following WPG treatment. In a rat AF-defect model, intradiscal WPG administration preserved disc height and T 2 -weighted MRI signal, reduced MMP13 while increasing Collagen I and Aggrecan expression, suppressed nuclear P-p65 and LCN2, and improved segment biomechanics—without eliciting adverse hematological or organ responses. Collectively, these findings establish that aligning molecular targeting (NF-κB–LCN2 modulation) with the pathophysiological context via ROS-gated delivery provides a synergistic strategy for AF repair and attenuation of IVDD progression.
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DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
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2025
·Vol. 10
·期 1
·1-19
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IF 52.7
Wang Baile,Liu Jie,Wang Qin,Arhatte Malika,Cheong Lai Yee,Glogowska Edyta,Jiang Xue,Chung Sookja Kim,Jin Leigang,Hu Qianxing,Wang Yu,Honoré Eric,Xu Aimin
With aging or osteoporosis, bone marrow adipogenesis is increased and inversely correlates with the loss of bone mass. Bone marrow adipocytes are derived from multipotent bone marrow mesenchymal stem cells (BMMSCs), which can differentiate into either fat or bone. BMMSCs are mechanosensitive cells, but how mechanical loading is implicated in the in vivo regulation of bone marrow adipogenesis and its impact on bone remodeling remain poorly understood. Here, we identify the mechanosensitive cationic channel Piezo1 in BMMSCs as a key suppressor of bone marrow adipogenesis by preventing local inflammation, thereby enhancing osteoblast differentiation and bone formation. Mice with a specific Piezo1 invalidation in BMMSCs exhibit osteoporosis and marrow adiposity, together with resistance to the beneficial effects of exercise on bone health. Accordingly, Piezo1-deficient BMMSCs in vitro preferentially differentiate into adipocytes rather than osteoblasts. Invalidation of Piezo1 in BMMSCs enhances the autocrine activation of CCR2 by Ccl2, which further induces lipocalin-2 (Lcn2) production via NF-κB activation, thereby promoting adipocyte differentiation. Conversely, Piezo1 opening induces Klf2 expression through CaMKII, preventing c-Jun activation, Ccl2 production and bone marrow adipogenesis. These findings demonstrate that Piezo1 activation in BMMSCs suppresses bone marrow adipogenesis to maintain bone strength by preventing the Ccl2-Lcn2 inflammatory autocrine loop, thus uncovering a previously unrecognized link between mechanotransduction, inflammation, and cell fate determination.
研究领域:
骨生物学
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干细胞生物学
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机械转导
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炎症与免疫
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代谢性骨病
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分子细胞生物学
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转化医学
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DOI
PubMed
高影响因子
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