FASEB JOURNAL
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2025
·Vol. 39
·期 3
·e70379
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IF 4.2
Jiancheng Yang,Qinghua Tang,Siyu Li,Lei Yang,Ming Yang,Qingmei Li,Yan Feng,Mingming Pan,Yuhong Zeng
The accumulation of intracellular reactive oxygen species (ROS) is widely recognized to stimulate the development of osteoclasts, a crucial factor in the onset of osteoporosis. The ROS scavenging capability of Prussian blue nanoparticles (PBNPs) is exceptional, and they possess excellent biocompatibility. However, the effects of PBNPs on osteoporosis remain unknown. Present study aimed to investigate whether PBNPs could inhibit osteoclast differentiation and prevent ovariectomy (OVX)-induced bone loss by suppressing ROS. In vitro experiments demonstrated that PBNPs attenuated osteoclastogenesis and downregulated the expression of osteoclast-related genes. Mechanistically, PBNPs reduce cellular ROS by blocking RANKL-induced ROS generation and increasing the expression of ROS scavenging enzymes, which in turn block the NF-κB, ERK, JNK, and p38 pathways, thereby reducing NFATc1 signaling. According to in vivo experimental results, OVX caused a significant rise in ROS in the bone marrow, an increase in osteoclastic number on the bone surface, and substantial bone loss; however, PBNPs significantly reduced ROS and successfully protected OVX-induced bone damages. In conclusion, this study showed for the first time that PBNPs prevented OVX-induced bone loss and attenuate osteoclastogenesis, indicating that PBNPs may be a viable alternative therapy for the management of osteoclast-associated bone disorders. Graphical Once RANKL binds to RANK on the cell membrane of BMMs, the NF-κB and MAPK pathways become activated, resulting in the amplification of NFATc1, which upregulates the expression of osteoclast-specific genes such as CTSK , Integrin αV , Atp6v0d2 , and MMP9 . These signaling events are mediated by the RANKL-induced ROS signaling. PBNPs decreased levels of ROS and mitigated these signaling pathways by decreasing ROS production and enhancing the expression of antioxidant enzymes. Consequently, PBNPs prevented osteoclastogenesis.
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ADVANCED FUNCTIONAL MATERIALS
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2025
·
IF 19
Yangyang Chen,Chan Xue,Feifei Ni,Binwu Hu,Miaoheng Yan,He Zhang,Yuxiang Hu,Xiaoyao Peng,Guangfang Li,Yu Han,Hongjian Liu,Zengwu Shao,Qin Wang,Yulong Wei
Annulus fibrosus (AF) injury plays a critical role in intervertebral disc degeneration (IVDD), with oxidative stress and extracellular matrix (ECM) imbalance being major pathogenic factors. However, effective repair methods are limited. In this study, an injectable photothermal hydrogel, Mn 3 O 4 @ChS-HA, composed of dopamine-grafted oxidized chondroitin sulfate (dop-OChS), adipic dihydrazide-modified hyaluronic acid (ADH-HA), and Mn 3 O 4 nanoparticles is constructed to repair AF damage. The Mn 3 O 4 @ChS-HA mimics the native intervertebral disc environment, offering excellent mechanical properties and strong adhesion to the AF defect site, while enabling long-term retention of Mn 3 O 4 nanoparticles. Mn 3 O 4 nanoparticles exhibit catalytic properties similar to those of superoxide dismutase, catalase, and glutathione peroxidase, efficiently scavenging reactive oxygen species and modulating ECM metabolism. In vitro and in vivo studies demonstrate that Mn 3 O 4 @ChS-HA significantly inhibits apoptosis, delays cell senescence, reduces inflammation, and promotes autophagy, facilitating AF repair. The hydrogel also restores disc height and maintained ECM integrity in a rat model of AF injury. Mild photothermal therapy (MPTT) further enhances these effects, supporting tissue regeneration and delaying the progression of IVDD. The MPTT-nanozyme-hydrogel system, Mn 3 O 4 @ChS-HA, exhibits various biological functions by regulating redox homeostasis and promoting tissue repair, highlighting the potential of this approach as a promising strategy for IVDD treatment.
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Biomaterials Advances
·
2025
·
IF 6
Zini Huang,Yihan Ma,Xinyi Yang,Xiaoping Yang,Yinjia Cheng,Aiqing Zhang
Persistent microbial infections and excessive reactive oxygen species (ROS) accumulation severely impede diabetic wound healing. Herein, we developed an ultrasound-switchable BiVO 4 /fullerene piezoelectric heterostructure via a one-pot solvothermal method, enabling on-demand transition between bactericidal action and ROS scavenging for treating infected diabetic wounds. Under 8-min ultrasound (US) irradiation, the heterojunction sonosensitizer leveraged piezoelectric polarization to generate substantial ROS in real-time through a narrowed energy band gap and enhanced charge carrier separation and migration efficiency, resulting in the disruption of bacterial membrane integrity and 99.9 % eradication of methicillin-resistant Staphylococcus aureus (MRSA). Upon US withdrawal, the sonosensitizer spontaneously transitioned to an antioxidative state through fullerene-mediated ROS scavenging, effectively neutralizing excess ROS and restoring cellular redox balance. In an MRSA-infected diabetic wound model, this ultrasound-responsive duality effectively suppressed bacterial proliferation, reduced inflammation, enhanced angiogenesis, and ultimately accelerated wound healing within 14 days. This ultrasound-switchable therapeutic strategy offers promising insights for managing drug-resistant infections and other ROS-mediated biomedical challenges.
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JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Kunpeng Liu,Binbin Jiao,Guan Zhang,Zhihua Gan,Shicong Lai,Zhenshan Ding,Qingsong Yu
Bladder cancer remains a significant clinical challenge, necessitating the development of innovative therapeutic strategies. Recent advancements have highlighted the potential of reactive oxygen species (ROS)-responsive drug delivery systems in cancer therapy. In this study, we introduce a novel treatment approach utilizing a ROS-responsive camptothecin (CPT) prodrug encapsulated within a chitosan nanocarrier, named CACPT. Cinnamaldehyde (CA), acting as a ROS generator, forms thioketal bonds with CPT to create a prodrug that responds selectively to the elevated ROS levels within the tumor microenvironment. Upon exposure to high ROS conditions, these thioketal bonds are cleaved, resulting in the simultaneous release of CPT and CA. The liberated CA further enhances ROS production, establishing a positive feedback loop that amplifies the therapeutic effect. The use of amphiphilic chitosan nanocarriers enhances the retention and penetration of the prodrug within bladder tissue, optimizing its therapeutic potential. Our experimental findings demonstrate that this self-enhanced ROS-responsive release promotes increased cellular uptake and significantly enhances the anticancer efficacy of CACPT. These results position CACPT as a promising candidate for intravesical therapy in bladder cancer, potentially overcoming current limitations in treatment options. The innovative combination of ROS-responsive mechanisms and chitosan nanocarriers represents a paradigm shift in bladder cancer therapeutics, offering a multifaceted approach with substantial promise for clinical translation.
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JOURNAL OF CONTROLLED RELEASE
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2025
·
IF 11.5
Zihao Teng,Chen Liu,Xiangfu Du,Yuchen Guo,Zhenkun Huang,Jingya Gu,Xiaohui Chen,Menghan Xiao,Shipeng Chen,Xiao-Bin Hao,Jingbo Qin,Shuaidong Huo
The intracellular balance of reactive oxygen species (ROS) is crucial for cancer cell survival and tumor development, with mitochondria playing a key role in maintaining this balance through antioxidant defenses. Despite the efficacy of ROS-modulating strategies in many tumors, certain ROS-tolerant malignancies, such as HepG2 cells, pose significant therapeutic challenges due to their robust antioxidant systems and unique redox microenvironments. In this work, we have developed a self-amplifying nanoprodrug (nCACT) designed to target ROS-tolerant tumor cells. nCACT is constructed from a prodrug conjugate that combines a glutathione (GSH)-depleting chemotherapeutic agent, a mitochondria-targeting moiety, and a ROS-stimulated amplifying linker. The nCACT leverages the enhanced permeability and retention effect for tumor accumulation and cellular uptake, followed by acid-activated drug release and mitochondrial targeting. By disrupting ROS defense mechanisms and inducing mitochondrial dysfunction, nCACT effectively elevates ROS levels and depletes GSH, suppressing cancer cell growth. Our findings demonstrate that nCACT represents a novel and powerful strategy for overcoming ROS resistance in cancer therapy, offering a promising avenue for treating ROS-tolerant malignancies.
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Advanced Science
·
2025
·
IF 14.1
Shiye Du,Qiang Wen,Ting Han,Jiongyu Ren,Mingyu Wang,Yunpeng Dai,Xiaoguang Ge,Lu Li,Junzhi Liu,Shi Gao
Radiotherapy-radiodynamic therapy (RT-RDT) has emerged as a promising approach due to its remarkable anticancer efficacy. However, hypoxic tumor microenvironment and insufficient energy deposition severely reduce the radiotherapy outcomes. Herein, lonidamine (LND)-loaded Fe(III) metal-Pt(II) porphyrin framework (FPTM-LP) is designed for radiosensitization through hypoxia alleviation and reactive oxygen species (ROS) amplification. Specifically, the high-Z element Pt effectively absorbs X-ray photons to generate •OH for RT while transferring X-ray energy to porphyrin (TCPP), which stimulates the generation of 1 O 2 for RDT. Moreover, by the inhibition of oxidative phosphorylation, the weak acidity and glutathione (GSH)-responsive release of LND achieves O 2 economization, which promotes the generation of ROS and stabilizes DNA damage. Intriguingly, Pt(II)TCPP exhibits the capability of O 2 concentration-dependent near infrared luminescence imaging-guided RT-RDT. Moreover, the decomposition of FPTM-LP under high concentration of GSH generates large amounts of Fe 2+ , leading to the augmented production of •OH via Fenton reactions. In brief, this work presents a radiosensitizer with a unique and efficient mechanism of self-monitoring hypoxia alleviation and increasing ROS levels for enhanced cancer RT-RDT. The radiosensitization potency of FPTM-LP is confirmed in tumor-bearing mice in vivo, proclaiming a new strategy for enhancing therapeutic efficacy and minimizing side effects.
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BIOORGANIC & MEDICINAL CHEMISTRY
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2025
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IF 3
Jiangye Zhang,Rui Cai,Changxu Ning,Zhongxiang Zhou,Yibo Zhang,Shisheng Wang,Yueqing Li,Xiuhan Guo
Ferroptosis is a newly discovered form of cell death that is closely related to the occurrence of various diseases, such as neurodegenerative diseases, cardiovascular and cerebrovascular ischemic damage, and organ fibrosis. Therefore, the discovery of new active compounds with ferroptosis inhibitory activity is regarded as a new strategy for the clinical treatment of these diseases. In this study, a multifunctional prodrug molecule PNX-B2 with a phenoxazine structure was designed based on the oxidative microenvironment characteristic of ferroptosis. PNX-B2 can recognize the ferroptosis-associated oxidative conditions and simultaneously release compounds with ferroptosis-inhibitory activity. Moreover, it integrates diagnostic and therapeutic functions and offers a fluorescent indication of the ferroptosis microenvironment. PNX-B2 has demonstrated excellent ferroptosis-inhibitory activity with an EC 50 value of 1.7 nM. This intelligent multifunctional compound shows great potential as a novel clinical agent for ferroptosis inhibition and presents broad prospects for future development.
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Fundamental Research
·
2022
·
IF 0
Yan Zhang,Dou Du,Chao Fang,Xin Yu,Yujia Fang,Xinyu Liu,Di Ou,Haohao Yin,Hui Liu,Taixia Wang,Lu Lu,Xiaolong Li,Kun Zhang
Post-transcriptional epigenetic modifications provide numerous implications for tumor progression, metastasis and recurrence, which also pose resistances to reactive oxygen species (ROS)-based anti-tumor. Herein, we proposed an epigenetic deubiquitination disruption strategy to disarm the ubiquitination-deubiquitination balance-induced resistances to ROS production and ROS-based anti-tumor action for potentiating sonodynamic treatment (SDT) efficiency. To end it, porphyrin-derived metal-organic framework (MOF) sonocatalytic nanoplatforms were developed to load deubiquitination inhibitors (i.e., Auranofin). Ultrasound-triggered Auranofin release from [email protected] has been validated to blockade the deubiquitinating process and drive proteasome-mediated target protein degradation. The epigenetic deubiquitination disruption not only synergized with MOF-mediated sonocatalytic ROS production, but also inactivate deubiquitinating enzymes, blockade the deubiquitination process and further remove these resistances, both of which mutually behaved as reciprocal impetuses to significantly magnify SDT outcomes against liver cancers. Such a deubiquitination-engineered disruption approach finds an unprecedented pathway to disarm deubiquitination-induced resistances to SDT and other ROS-based anti-tumor means, which also enlightens us to establish other post-transcriptional epigenetic modification disruption strategies to re-program the tumor microenvironment and elevate the anti-tumor efficiency of various treatment methods (e.g., immunotherapy).
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2019
·Vol. 24
·期 1
·50-60
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IF 4.658
Hongchao He,Ran Zhuo,Jun Dai,Xiaojing Wang,Xin Huang,Haofei Wang,Danfeng Xu
Renal cell carcinoma (RCC) is a heterogeneous histological disease and it is one of the most common kidney cancer. The treatment of RCC has been improved for the past few years, but its mortality still remains high. Chelerythrine (CHE) is a natural benzo[c]phenanthridine alkaloid and a widely used broad-range protein kinase C inhibitor which has anti-cancer effect on various types of human cancer cells. However, its effect on RCC has not been fully elucidated. In this study, we evaluated the effect and mechanism of CHE on RCC cells. Our study showed that CHE induced colony formation inhibition and G2/M cell cycle arrest in a dose-dependent manner in RCC cells. In addition, CHE increased cellular ROS level, leading to endoplasmic reticulum (ER) stress, inactivating STAT3 activities and inducing apoptosis in RCC cells which were suppressed by NAC, a special ROS inhibitor. We further found that both knockdown of ATF4 protein and overexpression of STAT3 protein could reduce CHE-induced apoptosis in Caki cells. These results demonstrated that the apoptosis induced by CHE was mediated by ROS-caused ER stress and STAT3 inactivation. Collectively, our studies provided support for CHE as a potential new therapeutic agent for the management of RCC.
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FOOD RESEARCH INTERNATIONAL
·
2025
·
IF 8
Kailin Li,Junyue Lin,Jingyan Liu,Yang Yang,Peng Zhang,Yanming Zhong,Sizhi Wu,Zhidan Lin,Lin Cao
In the global food waste crisis, perishable fruits contribute significantly to global food losses. In this study, a novel PU-CA composite film was synthesized using Polycaprolactone triol (PCL) and isophorone diisocyanate (IPDI) as the matrix, with chlorogenic acid (CA) added. The mechanical properties, hydrophobicity, antibacterial activity, and antioxidant capacity of film were characterized. The results showed that when the CA content was 6 wt%, the elongation at break of the film reached 450.35 %, and its tensile strength increased by 173.96 % compared to pure PU film. The PU-CA composite film exhibited 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-Azano-bis (3-ethylbenzothiazo-line-6-sulfonic acid) diammonium salt (ABTS) radical scavenging rates of 86.73 % and 75.40 %, respectively. Meanwhile, it exhibited antibacterial activity against Escherichia coli ( E. coli ) and Staphylococcus aureus ( S. aureus ), as well as biocompatibility (cell viability >90 %). Further grape preservation tests confirmed that the PU-CA composite film can effectively reduce the weight loss rate of grapes from 14 % to 2 % over an 8-day storage period, thereby extending their shelf life. These findings suggest that PU-CA composite films have broad application prospects in grape preservation packaging.
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International Journal of Nanomedicine
·
2025
·
IF 6.5
Quan Li,Haijun Sun,Xinjing Zhang,Yani Chen,Zhifeng Wu,Maohong Xia,Lu Sun,Weigang Shi,Zhaorui Sun,Wei Li,Lili Ding
Background Sepsis-associated acute lung injury (SALI) has high mortality, largely driven by a damaging cycle of oxidative stress and inflammation, with a lack of effective treatments. To address this, a novel biomimetic nanodrug was developed. It uses an amphiphilic copolymer (PT) to encapsulate the antioxidant/anti-inflammatory agent carnosic acid (CA), forming PT@CA micelles. These micelles are then coated with M2 macrophage membranes (MM) to create MM@PT@CA. Compared to traditional liposomes, the macrophage membrane has better inflammatory targeting and biological safety.Methods The PT copolymer was synthesized by grafting thioctic acid onto polylysine. CA was encapsulated via anti-solvent precipitation to form PT@CA, which was subsequently coated with M2 macrophage membranes via co-extrusion to yield the final bionic nanomicelle, MM@PT@CA. The system’s ROS-responsive drug release, antioxidant, and antibacterial activities were characterized. Its biocompatibility, ability to scavenge cellular ROS, anti-inflammatory effects, and promotion of M2 macrophage polarization were assessed in vitro. Therapeutic efficacy was further evaluated in a mouse model of sepsis-induced lung injury.Results MM@PT@CA demonstrated significant multifunctional efficacy across a series of experiments. In vitro, it scavenged DPPH and ABTS radicals by 74.07% and 91.47%, respectively, and inhibited the growth of Staphylococcus aureus and Escherichia coli. It was efficiently taken up by cells and accumulated at inflammatory sites. Moreover, it exhibited excellent biocompatibility, remarkably restoring cell viability under oxidative stress from 48.70% to 93.85% while down-regulating pro-inflammatory factors. In vivo, MM@PT@CA treatment reduced apoptosis from 28.79% to 5.49%. Notably, the progression of SALI was effectively halted, which was attributed to its ability to modulate macrophage polarization and inhibit the pro-inflammatory cytokine storm.Conclusion The developed bionic nanomicelle targets inflammation, combats infection and oxidative stress, and ultimately alleviates SALI. These features highlight MM@PT@CA promising therapeutic potential for the treatment of SALI.
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INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2018
·Vol. 42
·期 4
·1925-1934
·
IF 2.784
Yunfei Ma,Tuo Tang,Lili Sheng,Ziqian Wang,Hong Tao,Qing Zhang,Yao Zhang,Zhilin Qi
The anti‑inflammatory effects of aloin, a bioactive ingredient extracted from Aloe vera, have been described previously. The present study aimed to assess these effects and explore the underlying molecular mechanisms. RAW264.7 cells were incubated with different doses of aloin (100, 150 and 200 µg/ml) and lipopolysaccharide (LPS; 100 ng/ml) for the indicated times. Then, inducible nitric oxide synthase (iNOS) and cyclooxygenase‑2 expression levels were detected by western blot analysis and reverse transcription polymerase chain reaction (RT‑PCR).The concentrations of inflammatory cytokines in the cell culture supernatant were determined by ELISA. Total nitric oxide (NO) assay and reactive oxygen species (ROS) kits were used to detect NO and ROS levels, respectively. Mitogen‑activated protein kinase, nuclear factor κB and Janus kinase‑signal transducer and activator of transcription (JAK‑STAT) pathway activation were verified by western blot analysis. Confocal and nucleocytoplasmic separation experiments were used to detect STAT nuclear translocation. It was identified that aloin decreased the level of LPS‑induced iNOS expression, inhibiting the release of interleukin (IL)‑1β, IL‑6, tumour necrosis factor‑α and NO dose‑dependently. Mechanistically, aloin suppressed LPS‑induced JAK1‑STAT1/3 activation and STAT1/3 nuclear translocation. Additionally, LPS‑induced ROS production was inhibited by aloin. Collectively, these data suggest that aloin attenuated LPS‑induced inflammation by inhibiting ROS‑mediated activation of the JAK1‑STAT1/3 signalling pathway, thereby inhibiting the nuclear translocation of STAT1/3 in RAW264.7 cells. The present study provides an experimental basis for the clinical application of aloin in inflammatory‑associated diseases.
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