International Journal of Nanomedicine
·
2023
·
IF 8
Kai Dong,Qiuya Lei,Runhao Guo,Xianglong Wu,Yanni Zhang,Ning Cui,Jian-Yu Shi,Tingli Lu
Purpose: The levels of reactive oxygen species (ROS) in tumor cells are much higher than that in normal cells, and rise rapidly under the influence of exogenous or endogenous inducing factors, eventually leading to the apoptosis of tumor cells. Therefore, this study prepared a dual pH/reducing-responsive poly (N-isopropylacrylamide-co-Cinnamaldehyde-co-D-α-tocopheryl polyethylene glycol 1000 succinate, PssNCT) nanogels, which employed two exogenous ROS inducers, cinnamaldehyde (CA) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), to selectively induce apoptosis by regulating ROS levels in tumor cells.Methods: The PssNCT nanogels were prepared by the free radical precipitation polymerization under the crosslink between pH-sensitive hydrazone and reducing-sensitive disulfide bonds, followed by the physicochemical and morphological characteristics investigations. Plasma stability, dual pH/reducing responsive degradation and in vitro release were also assessed. In cell experiments, cytotoxicity in different cells were first detected. The intracellular ROS levels and mitochondrial functions of tumor cells were then evaluated. Moreover, the apoptosis and western-blot assays were employed to verify the association between ROS levels elevation and apoptosis in tumor cells.Results: The nanogels exhibited a round-like hollow structure with the diameter smaller than 200nm. The nanogels were stable in plasma, while showed rapid degradation in acidic and reducing environments, thus achieving significant release of CA and TPGS in these media. Furthermore, the sufficient amplification of ROS signals was induced by the synergistically function of CA and TPGS on mitochondria, which resulted in the opening of the mitochondrial apoptotic pathway and enhanced cytotoxicity on MCF-7 cells. However, nanogels barely affected L929 cells owing to their lower intracellular ROS basal levels.Conclusion: The specific ROS regulation method achieved by these nanogels could be explored to selectively kill tumor cells according to the difference of ROS signals in different kinds of cells.
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JOURNAL OF BIOLOGICAL CHEMISTRY
·
2021
·
IF 5.157
Lei Chen,Miao Hao,Jingmin Yan,Lin Sun,Guihua Tai,Hairong Cheng,Yifa Zhou
Heat-modified citrus pectin, a water-soluble indigestible polysaccharide fiber derived from citrus fruits and modified by temperature treatment, has been reported to exhibit anticancer effects. However, the bioactive fractions and their mechanisms remain unclear. In this current study, we isolated an active compound, trans-4,5-dihydroxy-2-cyclopentene-l-one (DHCP), from heat-treated citrus pectin, and found that is induces cell death in colon cancer cells via induction of mitochondrial ROS. On the molecular level, DHCP triggers ROS production by inhibiting the activity of succinate ubiquinone reductase (SQR) in mitochondrial complex II. Furthermore, cytotoxicity, apoptotic activity, and activation of caspase cascades were determined in HCT116 and HT-29 cell-based systems, the results indicated that DHCP enhances the sensitivity of cancer cells to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), with DHCP-induced ROS accounting for the synergistic effect between DHCP and TRAIL. Furthermore, the combination of DHCP and TRAIL inhibits the growth of HCT116 and HT-29 xenografts synergistically. ROS significantly increases the expression of TRAIL death receptor 5 (DR5) via the p53 and C/EBP homologous protein pathways. Collectively, our findings indicate that DHCP has a favorable toxicity profile and is a new TRAIL sensitizer that shows promise in the development of pectin-based pharmaceuticals, nutraceuticals, and dietary agents aimed at combating human colon cancer.
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BIOMATERIALS
·
2022
·
IF 15.304
Xuan Li,Kun Xu,Ye He,Bailong Tao,Ke Li,Chuanchuan Lin,Jingwei Hu,Jing Wu,Yi Wu,Shaopeng Liu,Peng Liu,Huaiyu Wang,Kaiyong Cai
Ideal titanium implants are required to participate in bone repair actively to improve in situ osteointegration. However, the traditional surface functionalization methods of titanium implants are difficult to both achieve the active regulation and long-term stability of bioactive components. Here, a novel functionalized titanium which loaded with thymosin β4 (Tβ4) and covered by a hydrogel coating was designed and evaluated. A strong adhesion between the coating and the titanium substrate was realized by the synergistic action of borate ester bonds and surface topological structure. The hydrogel coating also achieved an in vivo adhesion between implant and tissue through hydrogen bonds and borate bonds. In addition, based on the ROS response property of borate bonds, the implant can release Tβ4 in response to the immune reaction of bone healing by regulating the polarization of macrophages, thereby reducing the fibrosis formation around the implant interface and promoting vascularization and osteointegration of bone defects.
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BIOMATERIALS
·
2022
·
IF 15.304
Maohua Chen,Menghuan Li,Yujia Wei,Chencheng Xue,Maowen Chen,Yang Fei,Lu Tan,Zhong Luo,Kaiyong Cai,Yan Hu
Bioenergy (ATP) is essentially required for supporting the osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs). However, factors such as high ROS levels and decreased glucose metabolism severely limit the bioenergy production in osteoporotic MSCs . We have prepared CaCO 3 -Quercetin- chromium (CaCO 3 -Qu-Cr) nanoparticles via ion coordination and packaged them into ROS-responsive gelatin/chitosan coating on titanium surface (Ti/Gel/CaCO 3 -Qu-Cr), aiming to improve the ATP production and cell mineralization by ameliorating ROS levels via Qu-mediated antioxidative effect and the promotional effect of Qu-Cr combination on glucose metabolism. Characterization results confirmed that Ti/Gel/CaCO 3 -Qu-Cr could be degraded in an ROS-responsive manner to release CaCO 3 -Qu-Cr nanoparticles continuously and eliminate excessive ROS in both the MSCs and microenvironment . Meanwhile, Ti/Gel/CaCO 3 -Qu-Cr significantly increased the glucose uptake and metabolism in osteoporotic MSCs and boosted their ATP and citrate production. This study laid the foundation for the development of functional titanium-based implants for the improvement of osteoporotic osseointegration .
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Advanced Science
·
2023
·
IF 15.1
Huiyun Li,Yusong Yuan,Lingpu Zhang,Chun Xu,Hailin Xu,Zhiwei Chen
Osteoarthritis (OA) is a chronic joint disease characterized by synovitis and joint cartilage destruction. The severity of OA is highly associated with the imbalance between M1 and M2 synovial macrophages. In this study, a novel strategy is designed to modulate macrophage polarization by reducing intracellular reactive oxygen species (ROS) levels and regulating mitochondrial function. A ROS-responsive polymer is synthesized to self-assemble with astaxanthin and autophagy activator rapamycin to form nanoparticles (NP@Poly RHAPM ). In vitro experiments show that NP@Poly RHAPM significantly reduced intracellular ROS levels. Furthermore, NP@Poly RHAPM restored mitochondrial membrane potential, increased glutathione (GSH) levels, and promoted intracellular autophagy, hence successfully repolarizing M1 macrophages into the M2 phenotype. This repolarization enhanced chondrocyte proliferation and vitality while inhibiting apoptosis. In vivo experiments utilizing an anterior cruciate ligament transection (ACLT)-induced OA mouse model revealed the anti-inflammatory and cartilage-protective effects of NP@Poly RHAPM , effectively mitigating OA progression. Consequently, the findings suggest that intra-articular delivery of ROS-responsive nanocarrier systems holds significant promise as a potential and effective therapeutic strategy for OA treatment.
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SENSORS AND ACTUATORS B-CHEMICAL
·
2024
·
IF 8
Xiaoyan Huang,Wanlu Sun,Yanyan Zhu,Chao Zhao,Baojin Tan,Hai-Yan Wang,Yi Liu
Photodynamic therapy (PDT) could induce apoptosis by releasing reactive oxygen species (ROS) to treat tumor. Application of pH/light dual-activated nanoparticles could generate ROS in the acidic tumor microenvironment under 808 nm laser irradiation for precise treatment. L-arginine (L-Arg) triggered by ROS is an efficient nitric oxide (NO) donor for gas therapy. In addition, it is reported that peroxynitrite (ONOO - ) produced by rapid reaction of ROS and NO could sensitize PDT and induce apoptosis for synergistic treatment. Herein, we developed the L-Arg loaded pH/light dual-activated PEGylated photosensitizer for self-assembly into nanoparticles named Rho-Arg. As measured by fluorescence spectroscopy, the pKa of Rho-Arg was 5.5, which is suitable for applying in the tumor microenvironment. The nanoplatform was firstly activated under the acidic condition of tumor, and then illuminated by 808 nm laser to controllably release ROS, and sequentially produced NO and ONOO - . In conclusion, the Rho-Arg nanoplatform may provide a promising synergistic therapy tool for tumor treatment.
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CURRENT MEDICINAL CHEMISTRY
·
2024
·
IF 3.5
Gan Xin,Xie Jingwen,Dong Zhaojun,Wu Yuna,Zeng Xiaoqing,Yang Zhenzhen,Liu Bo,Zhu Min,Wang Bozhen,Li Wulan,Wang Ledan,Zhang Huajie,Wu Jianzhang,Hu Yue
Background: Pyroptosis, a cell death process triggered by chemotherapy drugs, has
emerged as a highly promising mechanism for combating tumors in recent years. As the lead of
new drugs, natural products play an important role in the discovery of anticancer drugs. Compared
to other natural products, the medicine food homologous natural products (MFHNP) exhibit a superior
safety profile. Among a series of MFHNP molecular skeletons, this study found that only
benzylideneacetophenone (1) could induce cancer cell pyroptosis. However, the anti-cancer activity
of 1 remains to be improved.
Aims: This study aimed to find a pyroptosis inducer with highly effective antitumor activity by
modifying the chalcone structure.
Methods: To examine the effect of the Michael receptor in compound 1 on the induction of pyroptosis,
several analogs were synthesized by modifying the Michael acceptor. Subsequently, the anticancer
activity was tested by MTT assay, and morphological indications of pyroptosis were observed
in human lung carcinoma NCI-H460 and human ovarian cancer CP-70 cell lines. Furthermore,
to improve the activity of the chalcone skeleton, the anticancer group 3,4,5-
trimethoxyphenyl was incorporated into the phenyl ring. Subsequently, compounds 2-22 were designed,
synthesized, and screened in human lung cancer cells (NCI-H460, H1975, and A549). Additionally,
a quantitative structure-activity relationship (QSAR) model was established using the
eXtreme Gradient Boosting (XGBoost) machine learning library to identify the pharmacophore.
Furthermore, both in vitro and in vivo experiments were conducted to investigate the molecular
mechanisms of pyroptosis induced by the active compound.
Results: α, β-unsaturated ketone was the functional group of the chalcone skeleton and played a
pivotal role in inducing cancer cell pyroptosis. QSAR models showed that the regression coefficients
(R2) were 0.992 (A549 cells), 0.990 (NCI-H460 cells), and 0.998 (H1975 cells). Among these
compounds, compound 7 was selected to be the active compound. Moreover, compound 7 was
found to induce pyroptosis in lung cancer cells by upregulating the expression of CHOP by increasing
the ROS level. Furthermore, it effectively suppressed the growth of lung cancer xenograft
tumors.
Conclusion: Compound 7 exhibits antineoplastic activity by regulating the ROS/ER stress/pyroptosis
axis and is a kind of promising pyroptosis inducer.
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Pharmaceutics
·
2024
·Vol. 16
·期 7
·936
·
IF 4.9
Peng Chen,Zhihui Wang,Xinmo Wang,Junni Gong,Ju Sheng,Yufei Pan,Dandan Zhu,Xiaoxuan Liu
Small interfering RNA (siRNA) therapeutics, characterized by high specificity, potency, and durability, hold great promise in the treatment of cancer and other diseases. However, the clinic implementation of siRNA therapeutics critically depends on the safe and on–demand delivery of siRNA to the target cells. Here, we reported a family of ferrocenyl amphiphilic dendrimers (Fc-AmDs) for on–demand delivery of siRNA in response to the high ROS content in cancer cells. These dendrimers bear ROS–sensitive ferrocene moieties in the hydrophobic components and positively chargeable poly(amidoamine) dendrons as the hydrophilic entities, possessing favorable safety profiles and ROS responsive properties. One of these ferrocenyl amphiphilic dendrimers,Fc-C8-AmD 8A, outperforms in siRNA delivery, benefiting from its optimal balance of hydrophobicity and hydrophilicity. Its ROS feature facilitates specific and efficient disassembly of its complex with siRNA in ROS–rich cancer cells for effective siRNA delivery and gene silencing. Moreover,Fc-C8-AmD 8Aalso integrates the features and beneficial properties of both lipid and dendrimer vectors. Therefore, it represents a novel on–demand delivery system for cancer cell–specific siRNA delivery. This work opens new perspectives for designing self–assembly nanosystems for on–demand drug delivery.
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CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Hongyan Lu,Ying Cheng,Xiangling Pu,Xingtao Zhao,Ruolan Li,Ruiqi Sun,Xiaoman Xie,Mingyue Wu,Shuo Zhang,Qiong Pan,Jin Chai
Simultaneously alleviating oxidative stress and remodeling inflammatory microenvironment holds great promise for treating inflammatory bowel disease (IBD). Nevertheless, the efficacy of conventional therapies remains limited by poor targeting, insufficient modulation of the inflammatory microenvironment and serious adverse effects. Here, inspired by the intrinsic biological properties of metal-curcumin (Cur) complexes, a nanozyme-mediated ion-exchange strategy was proposed to enhance the targeted therapeutic effect of Cur for IBD. Specifically, copper-doped mesoporous polydopamine nanoparticles (Cu-mPDA) with dual enzyme-like activities were served as drug carriers to encapsulate water-soluble zinc-curcumin (Zn-Cur) and further modified with hyaluronic acid (HA), yielding Zn-Cur/Cu-mPDA@HA. Encouragingly, Zn-Cur/Cu-mPDA@HA could degrade in inflammatory microenvironment, releasing Zn-Cur and Cu 2+ , which subsequently in situ generate Cu-Cur with high antioxidant activity by ion-exchange reaction. Notably, Zn-Cur/Cu-mPDA@HA not only exhibited favorable targeting specificity toward M1 macrophages in inflamed colon tissues, but also displayed enhanced abilities to scavenge ROS, inhibit pro-inflammatory factors secretion and promote macrophages repolarization from the pro-inflammatory M1 state to the anti-inflammatory M2 subtype. Mechanistically, Zn-Cur/Cu-mPDA@HA suppressed the TLR4/MyD88/NF-κB pathway, breaking the inflammation-free radical vicious cycle, thereby attenuating chronic inflammation and fostering a favorable microenvironment for intestinal barrier restoration. Such a nanozyme-mediated ion-exchange and in situ drug generation strategy offers a new insight for designing nanomedicines for the treatment of IBD and other inflammatory diseases.
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BMC Pharmacology & Toxicology
·
2025
·Vol. 26
·期 1
·1-13
·
IF 2.7
Fu Wenying,Lu Hui,Yan Ying,Shu Chongchong,Xu Chenxin,Chen Yinghua,Xia Yiqun,Chen Jundixia,Chen Yunzhi,Zou Peng,Cui Ri,Ni Daoyong
Section
Background
Lung cancer continues to rank as a leading cause of cancer-related mortality worldwide. Despite notable advances in medical research, therapeutic options for advanced-stage lung cancer remain inadequate. Heat shock protein 90 (HSP90) has been identified as a potential therapeutic target in multiple malignancies, such as lung and colon cancers, owing to its pivotal role in stabilizing numerous oncoproteins. Nonetheless, the clinical application of HSP90 inhibitors has faced challenges, including suboptimal efficacy and the development of resistance mechanisms. B-AP15 is a promising small molecule in cancer therapy that functions by inhibiting deubiquitinating enzymes, which regulate protein degradation through the proteasome pathway. In this study, we aim to investigate its combinatorial activity with the HSP90 inhibitor tanespimycin (TAU) in lung cancer cells.
Section
Methods
The levels of the specified molecules were measured by Western blot analysis. Reactive oxygen species (ROS) levels were determined using the 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. 53BP1 foci formation and C/EBP homologous protein (CHOP) expression were assessed by immunofluorescence. Autophagic flux was monitored using mRFP-GFP-tagged microtubule-associated protein 1 light chain 3 (LC3) lentivirus.
Section
Results
Our findings reveal that the combination of TAU and B-AP15 induces significant synergistic antitumor effects, characterized by substantial accumulation of ROS. This ROS accumulation serves as a crucial mediator of the enhanced therapeutic response elicited by the combination treatment. Mechanistic analyses further demonstrated that the combined treatment induces cell death via activation of endoplasmic reticulum (ER) stress and the c-Jun N-terminal kinase (JNK) pathway.
Section
Conclusion
In summary, our study provides robust evidence supporting the potential of combining TAU with B-AP15 as a viable therapeutic option for lung cancer treatment.
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Yingying Pan,Jiaying Lou,Yuqi Wang,Rongfang Dai,Miwen Zou,Danni Ma,Shengzhang Chen,Jinghao Zhou,Binyan Chen,Xiaoqiong Jiang,Pan Huang,Huaqiong Li,Fuman Cai,Dejun Yang
Pressure injuries (PIs) have emerged as a significant burden on individuals and society, lacking effective treatment due to the compromised wound microenvironment resulting from ischemia-reperfusion injury. The accumulation of excessive reactive oxygen species (ROS) is the core mechanism of delayed wound healing, which triggers a cascade of harmful events, including chronic inflammation, impaired angiogenesis, and abnormal ECM degradation. Epigallocatechin gallate (EGCG) is a natural antioxidant that has been reported to promote angiogenesis and suppress inflammation, but its application is limited by low bioavailability. Herein, we employed EGCG as a crosslinker to develop a multifunctional HA-PBA/EGCG hydrogel (abbreviated as HPE) to enhance EGCG bioavailability for PIs treatment. Specifically, HPE hydrogel was prepared by the formation of the boronic ester bonds through the reaction of EGCG and phenylboronic acid-modified hyaluronic acid, and evaluated for self-healing, injectability, antioxidant activity, biocompatibility, and pH- and ROS-responsiveness. In vitro, HPE hydrogel effectively improved cell migration and protected NIH3T3 and HUVECs from TBHP-induced oxidative damage. These effects collectively improved the PI microenvironment in vivo, activated the antioxidant Nrf2/HO-1/NQO1 pathway to reduce oxidative stress damage, promoted M2 macrophage polarization, suppressed inflammation, improved neovascularization, and enhanced collagen deposition and remodeling, accelerating tissue regeneration and wound closure. In summary, these findings highlight the pronounced therapeutic potential and effectiveness of this multifunctional hydrogel in overcoming the multifaceted challenges of chronic PI wounds.
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Nature Communications
·
2026
·
IF 18.1
Mao Congyang,Jin Wanyu,Dou Limeng,Guo Tong,Huang Jin,Wang Yi,Liu Xiangmei,Wu Shuilin,Qiao Wei,Xiang Yiming,Zhu Yizhou,Wu Jun,Yeung Kelvin Wai Kwok
The pandemic-scale progression of type 2 diabetes mellitus (T2DM) necessitates innovative interventions targeting the pathogenic triad of insulin resistance, dysregulation of lipid metabolism, and gut microbiome dysbiosis. Here, we report a synthetically bioengineered probiotic consortium (REcN-F/Ca) developed through directed metabolic adaptations of Escherichia coli Nissle 1917 (EcN) under iterative hydrogen peroxide selection, subsequently functionalized with fructooligosaccharide-calcium carbonate composites. REcN-F/Ca exhibits enhanced reactive oxygen species tolerance through upregulated antioxidant enzymes and hydrogen sulfide-mediated redox balancing, alongside improved gastrointestinal survivability. In high-fat diet-induced obese male mice, REcN-F/Ca restores gut microbiota diversity, enriches butyrogenic taxa (Lachnospiraceae and Blautia ), and rescues short-chain fatty acids depletion. Transcriptomic profiling reveals PPAR signaling activation, driving lipid metabolism and suppressing adipose inflammation. These effects translate to systemic metabolic improvements with attenuated weight gain (−25.4%), restored glucose homeostasis, and reduced insulin resistance (HOMA-IR: −73.2%) in the obesity and T2DM murine model. Our findings establish REcN-F/Ca as a synthetically engineered probiotic that simultaneously corrects intestinal ecological perturbations and reverses host metabolic dysfunction, proposing a paradigm for metabolic syndrome management.
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