ACS Applied Bio Materials
·
2025
·
IF 4.7
Ji Xia,Jin Huang,Yixiao Yan,Chenxin Jian,Jiansheng He,Nisha Wang,Lei Shi,Qiyang Ding,Hao Tian,Wei Gao
Mitochondrial damage occurs as an initial event following ischemic onset, and the extent of mitochondrial dysfunction is highly correlated to the severity of ischemia-induced cell death. Once appropriate therapeutic interventions are provided, the ischemic tissue can be salvaged, which is of great significance in achieving better neurological outcomes. Herein, we developed a nanosized starch as a targeting nanoplatform, featuring effective blood-brain barrier (BBB) penetration through lactoferrin-mediated transcytosis. Notably, the nanostarch-based delivery of Mdivi-1 and Alda-1 enables controlled release in the acidic lysosome of neurons, effectively inhibiting the pathological mitochondrial fission and metabolizing toxic aldehydes, thereby creating protective effects on maintaining mitochondrial function. Moreover, we demonstrated that mitochondrial protection induces a transition from activated pro-death responses to a pro-survival state by reducing the release of pro-apoptotic proteins, significantly contributing to the long-term recovery of neurological function. Overall, our nanostarch provided an in-depth understanding of the delivery of mitochondrial protectants and underscored the potential and utility of mitochondrial protection for ischemic stroke via minimizing neuronal apoptosis.
研究领域:
神经科学
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药理学
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生物医学工程
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PubMed
高影响因子
LIFE SCIENCES
·
2024
·
IF 5.2
Yi Xiao,Jiahe Zhang,Xinran Li,Pinxuan Liu,Bo Gou,Zeyu Gao,Moshi Song
Background The role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is multifaceted, paradoxically promoting both cell survival and cell death across multiple organs. However, its impact on lung homeostasis remains elusive. Here, we investigate the function of DNA-PKcs in mouse lungs, aiming to elucidate its role for lung abnormalities associated with DNA-PKcs deficiency. Materials and methods Histological assessment and immunohistochemistry were used to reveal the pathological changes of the lungs in DNA-PKcs-deficient mice. Transcriptomic analysis identified differentially expressed genes and pathways in DNA-PKcs-deficient lungs. Furthermore, mitochondrial dysfunction induced by DNA-PKcs deficiency was investigated by qPCR and immunoblotting. Mouse primary lung fibroblasts were used to evaluate the potential therapeutic effect of inhibiting mitochondrial fission with Mdivi-1. Key findings In DNA-PKcs-deficient mouse lungs, we observed pathological changes including alveolar septal thickening, capillary congestion and hemorrhage, along with lung cell proliferation. Transcriptome analysis revealed an upregulation of the reactive oxygen species (ROS) biosynthesis process and the apoptotic signaling pathway caused by DNA-PKcs deficiency. Further investigations demonstrated that DNA-PKcs deficiency led to mitochondrial dysfunction and increased oxidative stress, along with increased cell apoptosis in the mouse lungs. Notably, we detected enhanced phosphorylation of the mitochondrial fission protein DRP1 in DNA-PKcs-deficient mouse lungs. Intriguingly, inhibiting mitochondrial fission using Mdivi-1 suppressed cell death in primary mouse lung fibroblasts with siRNA-mediated DNA-PKcs knockdown. Significance Our study provides insights into the crucial role of DNA-PKcs in sustaining lung homeostasis via the maintenance of mitochondrial functionality and provides a therapeutic strategy targeting mitochondrial fission against DNA-PKcs deficiency-associated lung diseases.
研究领域:
分子生物学
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细胞生物学
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肺生理学
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病理学
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PubMed
高影响因子
ADVANCED MATERIALS
·
2024
·
IF 27.4
Wen Li,Qi-Wen Chen,Jin-Xuan Fan,Zi-Yi Han,Wen-Fang Song,Xuan Zeng,Xian-Zheng Zhang
Due to inherent differences in cellular composition and metabolic behavior with host cells, tumor-harbored bacteria can discriminatorily affect tumor immune landscape. However, the mechanisms by which intracellular bacteria affect antigen presentation process between tumor cells and antigen-presenting cells (APCs) are largely unknown. The invasion behavior of attenuated Salmonella VNP20009 (VNP) into tumor cells is investigated and an attempt is made to modulate this behavior by modifying positively charged polymers on the surface of VNP. It is found that non-toxic chitosan oligosaccharide (COS) modified VNP (VNP@COS) bolsters the formation of gap junction between tumor cells and APCs by enhancing the ability of VNP to infect tumor cells. On this basis, a bacterial biohybrid is designed to promote in situ antigen cross-presentation through intracellular bacteria induced gap junction. This bacterial biohybrid also enhances the expression of major histocompatibility complex class I molecules on the surface of tumor cells through the incorporation of Mdivi-1 coupled with VNP@COS. This strategic integration serves to heighten the immunogenic exposure of tumor antigens; while, preserving the cytotoxic potency of T cells. A strategy is proposed to precisely controlling the function and local effects of microorganisms within tumors.
研究领域:
癌症生物学
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免疫学
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生物技术
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DOI
PubMed
高影响因子
Small
·
2023
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IF 13.3
Xiaodi Gong,Jing Wang,Linlin Yang,Lijuan Li,Xiaoyan Gao,Xiao Sun,Jingfeng Bai,Jichang Liu,Xin Pu,Yudong Wang
Chemodynamic therapy (CDT) relies on the tumor microenvironment (e.g., high H 2 O 2 level) responsive Fenton-like reactions to produce hydroxyl radicals (·OH) against tumors. However, endogenous H 2 O 2 is insufficient for effective chemodynamic responses. An NAD(P)H: quinone oxidoreductase 1 (NQO1) high catalase (CAT) low therapeutic window for the use of NQO1 bioactive drug β-lapachone (β-Lap) is first identified in endometrial cancer (EC). Accompanied by NADH depletion, NQO1 catalyzes β-Lap to produce excess H 2 O 2 and initiate oxidative stress, which selectively suppress NQO1 high EC cell proliferation, induce DNA double-strand breaks, and promote apoptosis. Moreover, shRNA-mediated NQO1 knockdown or dicoumarol rescues NQO1 high EC cells from β-Lap-induced cytotoxicity. Arginine-glycine-aspartic acid (RGD)-functionalized iron-based metal-organic frameworks (MOF(Fe)) further promote the conversion of the accumulated H 2 O 2 into highly oxidative ·OH, which in turn, exacerbates the oxidative damage to RGD-positive target cells. Furthermore, mitophagy inhibition by Mdivi-1 blocks a powerful antioxidant defense approach, ultimately ensuring the anti-tumor efficacy of stepwise-amplified reactive oxygen species signals. The tumor growth inhibition rate (TGI) is about 85.92%. However, the TGI of MOF(Fe)-based synergistic antitumor therapy decreases to only 50.46% in NQO1-deficient KLE tumors. Tumor-specific chemotherapy and CDT-triggered therapeutic modality present unprecedented therapeutic benefits in treating NQO1 high EC.
研究领域:
肿瘤学
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药学
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生物医学工程
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细胞生物学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2021
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IF 6.4
Xiaodi Gong,Xin Pu,Jing Wang,Linlin Yang,Yunxia Cui,Lijuan Li,Xiao Sun,Jichang Liu,Jingfeng Bai,Yudong Wang
Purpose Iron-based nanomaterials have recently been developed as excellent and potent Fenton reagents to reactive oxygen species (ROS) during chemodynamic therapy (CDT). The performance of the materials, however, can be impaired by the intrinsic antioxidant defense mechanism in organisms, such as autophagy. Methods The nanoscale metal-organic frameworks (nMOFs), nMIL-100 (Fe), were exploited and characterized. Also, the Fenton-like catalytic characteristics, anti-endometrial cancer (EC) effects and potential mechanisms of nMIL-100 (Fe) nanoparticles were investigated in vitro. Results The synthesized nMIL-100 (Fe) nanocatalyst catalyzed hydroxyl radicals (·OH) production in the presence of hydrogen peroxide (H 2 O 2 ) and simultaneously depleted intracellular glutathione (GSH). Combining with H 2 O 2 , nMIL-100 (Fe) nanoparticles exhibited enhanced cytotoxicity for EC cells, especially for progesterone treatment-insensitive KLE cells, probably due to relatively lower expression of the catalase gene. The accumulated ·OH initiated PTEN induced putative kinase 1 (PINK1)/E3 ubiquitin-protein ligase Parkin-mediated cytoprotective mitophagy in turn to partially rescue ·OH-induced cell apoptosis. Furthermore, both pretreatments of EC cells with siRNA-mediated Parkin knockdown and Mdivi-1 (a mitophagy inhibitor) addition were sufficient to ensure nMIL-100 (Fe) synergizing with H 2 O 2 -induced oxidative damages. Conclusion These results suggest that the degree of mitophagy should be taken into consideration to optimize therapeutic efficiency when developing ROS based-CDT for EC cancer therapies. Therefore, a nMIL-100 (Fe)-guided, elevated ROS and overwhelmed mitophagy-mediated therapeutic strategy may have greater promise for EC therapy compared with current treatment modalities.
研究领域:
纳米技术
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癌症研究
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细胞生物学
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治疗学
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肿瘤学
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PubMed
高影响因子
ACS Nano
·
2026
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IF 17.3
Hao Ling,Annan Liu,Yu Zhang,Quan Lin,Chunli Song
The vicious cycle between reactive oxygen species (ROS) burst and impaired mitochondria represents a core pathological driver in myocardial infarction (MI). Synergistically promoting ROS scavenging and enhancing mitophagy to achieve dual restoration of redox homeostasis and energy metabolism are crucial for the effective treatment of MI. To address this, we developed a biomimetic sesame cube-shaped selenium-doped Prussian blue nanozyme (SP) featuring Se0/Fe2+/Fe3+ active sites. By leveraging the superoxide dismutase (SOD)-like activity of the nanozyme, superoxide anions (·O2–) are converted into hydrogen peroxide (H2O2). Simultaneously, the material’s catalase (CAT)-mimetic activity further decomposes the resulting H2O2 into oxygen (O2) while cooperatively activating PINK1/Parkin-mediated mitophagy via selenium-enhanced electron transport. The nanozyme was subsequently integrated into a hydrogel to form the SP@Gel through dynamic Schiff base cross-linking between aldehyde-modified hyaluronic acid and amine-functionalized nanozyme. Upon injection into the infarcted myocardium, this hydrogel enables the sustained release of nanozymes. The SP@Gel exhibits excellent capabilities in promoting ROS scavenging and mitigating oxidative damage, thereby improving myocardial redox homeostasis. Furthermore, the SP@Gel enhances cardiac mitophagic flux and regulates this process via the PTEN-induced putative kinase 1 (PINK1)/Parkin/microtubule-associated protein 1 light chain 3 beta (LC3B) pathway, facilitating the restoration of mitochondrial structure and energy metabolism. These findings were further validated by metabolomics analyses. SP@Gel injection mediated remodeling of the MI microenvironment, resulting in significantly reduced infarct size, suppressed fibrosis, enhanced angiogenesis, and substantially improved cardiac function. This integrated nanozyme-hydrogel system represents a promising therapeutic strategy for MI, achieving synergistic treatment through the dual regulation of oxidative stress and mitochondrial quality control.
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高影响因子
METABOLIC BRAIN DISEASE
·
2025
·Vol. 40
·期 2
·1-16
·
IF 3.5
Yan Xiao-dan,Fan Rong-hua,Wang Yu,Duan Xiao-xu,Wei Xuan,Li Lin-sen,Yu Qing
Diabetic encephalopathy (DE) is a common complication of diabetes that may result in cognitive impairment. Currently, there is limited effective therapy for DE. Herein, we explored the beneficial effect of α-Asarone on DE and its potential mechanisms. DE was induced in Type 2 diabetes mellitus mice and high-glucose (HG)-exposed PC-12 cells. Cognitive function was evaluated by MWM test. Pathological changes in the brain tissues were observed by HE staining. Cell viability was detected by CCK-8. Apoptosis was assessed by Hoechst 33,342 staining, Annexin V/PI staining and TUNEL. Mitochondrial membrane potential was analyzed by JC-1 probe. ROS production was measured by DCFH-DA staining. Target protein levels were analyzed by Western blotting. Network pharmacology was used to elucidate the beneficial mechanisms of α‐Asarone in DE. Our study showed that α‐Asarone enhanced cell viability and suppressed apoptosis in HG-stimulated PC-12 cells. Furthermore, α‐Asarone relieved HG-induced reduction in mitochondrial membrane potential and ROS overproduction. In addition, mitophagy was triggered by α‐Asarone, which was responsible for the inhibitory effect of α‐Asarone on apoptosis and oxidative stress. Consistently, the in vivo experiments showed that α‐Asarone treatment relieved cognitive dysfunction, apoptosis, and oxidative stress of DE mice via mitophagy induction. However, inhibition of mitophagy by Mdivi-1 counteracted the beneficial action of α‐Asarone. Mechanistically, network pharmacology analysis identified 10 key targets of α‐Asarone. Molecular docking substantiated a strong affinity of α‐Asarone with CASP3, EGFR, NFKB1, and ESR1 proteins. Taken together, α‐Asarone protected against mitochondrial dysfunction, oxidative stress and apoptosis via activating mitophagy, thereby alleviating DE. Our findings suggest α‐Asarone as a potential drug for DE. Graphical
研究领域:
神经生物学
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药理学
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分子生物学
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高影响因子
DRUG DEVELOPMENT RESEARCH
·
2025
·Vol. 86
·期 7
·e70171
·
IF 4.2
Hao Ling,Chunli Song
Oleuropein (OLEU), a natural polyphenol, exhibits cardioprotective potential through mitochondrial modulation, yet its precise mechanisms remain elusive. This study elucidates OLEU's role in alleviating oxidative stress and regulating mitochondrial quality control via the PINK1/Parkin pathway. In vitro, H9C2 cardiomyocytes exposed to H₂O₂-induced oxidative stress were treated with OLEU (0–200 μM), and analyses included cell viability, ROS, SOD, MDA, ΔΨm, ATP, PINK1/Parkin expression and detection of Mitophagic Flux. In vivo, myocardial infarction (MI) was induced in SD rats via coronary ligation, followed by OLEU administration, with assessments of cardiac function, histopathology, and mitophagy using echocardiography, electron microscopy, immunohistochemistry and immunofluorescence. Results showed that OLEU (≤200 μM) dose-dependently restored cell viability, reduced ROS, and normalized SOD/MDA ( p < 0.05), while mitigating ΔΨm collapse and ATP depletion, indicating enhanced mitochondrial bioenergetics. OLEU upregulated PINK1/Parkin, promoting mitophagic clearance of damaged mitochondria, and metabolomic analysis revealed modulation of arginine/proline and lipid pathways. In MI rats, OLEU attenuated ROS, preserved myocardial structure, and improved cardiac function, supported by elevated mitophagy in electron microscopy. These findings demonstrate that OLEU protects cardiomyocytes by suppressing oxidative stress, stabilizing mitochondrial integrity, and activating PINK1/Parkin-mediated mitophagy, highlighting its therapeutic potential for myocardial injury and mitochondrial dysfunction.
研究领域:
心血管病学
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分子生物学
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药理学
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线粒体生物学
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氧化应激
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PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2026
·Vol. 63
·期 1
·454
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IF 5.5
Yu Jia-Xin,Zhang Wen-Xuan,Li Pu-Yu,Yang Yi-Liang,Huang Han-Chang
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized primarily by deterioration in memory, cognition, and learning ability. Its etiology is complex and influenced by multiple factors, including genetics and environment. With advancing research into mitochondrial function and mechanisms, impaired mitophagy has been proposed as a significant mechanism contributing to AD. The ApoE ε4 allele, a high-risk genetic factor for AD, may play a key role in disease pathogenesis by inducing mitophagy dysfunction and apoptosis. From the perspective of APOE gene polymorphisms, this study investigates abnormal changes in mitochondrial function and autophagy in humanized APOE4 mice primary astrocytes under oxidative stress, as well as the regulatory effect of curcumin (Cur) on mitophagy and oxidative stress-induced apoptosis, thereby exploring its potential to ameliorate AD through targeting mitophagy. Mitochondrial function analysis revealed that APOE4 expression reduced the antioxidant capacity and respiratory function of primary astrocytes, leading to mitochondrial membrane damage, intracellular reactive oxygen species (ROS) accumulation, and decreased ATP production. Curcumin effectively protected mitochondrial integrity, reduced the number of damaged mitochondria, improved overall mitochondrial function, and helped maintain mitochondrial homeostasis involving in PINK1/Parkin pathway. Regarding autophagy and apoptosis, curcumin was shown to restore autophagic flux, mitigate autophagy disruption caused by oxidative stress, and reverse early-stage apoptosis. Graphical
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高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Hao Ling,Yu Zhang,Chunli Song
Background: Chlorogenic acid (CGA) is a polyphenolic compound widely present in plants. It is primarily extracted from the leaves of Eucommia ulmoides, a native medicinal herb.Purpose: This study aimed to investigate the cardioprotective effects of CGA on myocardial infarction (MI) by modulating mitochondrial damage and mitophagy through the PINK1/Parkin signaling pathway.Methods: In vitro, H9C2 cardiomyocytes were treated with varying concentrations of CGA to assess cell viability, oxidative stress, mitochondrial function, and mitophagy markers (PINK1/Parkin) and mitophagic flux. In vivo, There are a total of 18 SD rats, which are randomly divided into Sham, MI, and CGA groups. MI was induced in SD rats via coronary artery ligation, followed by tail vein injection of CGA. Echocardiography, histological staining, electron microscopy, immunohistochemistry, Western blot (WB) and metabolomics analysis were conducted to evaluate cardiac function, tissue fibrosis, mitophagy, and metabolic changes.Results: CGA significantly improved cell viability and reduced oxidative stress in H9C2 cells. It also stabilized mitochondrial membrane potential, increased ATP levels, upregulated PINK1/Parkin expression and increase autophagy flux, Lysosomal inhibitor treatment elevates expression of Parkin, P62 and LC3-II. In MI rats, CGA reduced ROS levels, improved myocardial tissue integrity, reduced fibrosis, and enhanced cardiac function. Detected by electron microscopy, immunohistochemistry, and WB confirmed increased mitophagy in CGA-treated rats. Metabolomics analysis revealed significant alterations in metabolic pathways, particularly related to organic acids and amino acid metabolism.Conclusion: This study demonstrates that CGA exerts cardioprotective effects by modulating mitochondrial damage and promoting mitophagy through the PINK1/Parkin pathway. Our findings provide new insights into the therapeutic potential of CGA for MI treatment and suggest a promising natural compound for myocardial protection.
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高影响因子
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