EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
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2024
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IF 4.3
Ziming Liu,Sihui Li,Pengfei Xu,Huiqin Gan,Pengfei Yue,Shuying Xie,Zixia Zhang,Weifeng Zhu,Zhiyu Guan
Objective To prepare chitosan-loaded nanoparticles (NPs) that enhance the oral bioavailability of puerarin (Pur) and render it responsive to reactive oxygen species (ROS). Significance This research makes substantial progress towards the theory of intelligent drug delivery, offering a new reference for combining Pur with other natural medicinal active ingredients. Methods The acylation reaction between chitosan and ROS-sensitive 3-carboxyphenylboronic acid (PBA) was used to synthesise ROS-sensitive phenylboronylated chitosan (PBACS). Subsequently, PBACS-PBA-Pur-NPs and PBACS-TPP-Pur-NPs were prepared via ion gelation after the addition of PBA and sodium tripolyphosphate(TPP), respectively. The physicochemical and functional properties of both NPs were compared, and their differences were preliminarily studied through molecular docking. Results Reactive oxygen species-sensitive PBACS was successfully synthesised. Of the two NPs prepared, PBACS-TPP-Pur-NPs had a size of 127.2 ± 0.80 nm, polydispersity index (PDI) of 0.129 ± 0.0008, and an encapsulation rate of 95.75 ± 0.387%, whereas PBACS-PBA-Pur-NPs had a size of 149.8 ± 0.1414 nm, PDI of 0.389 ± 0.0012, and an encapsulation rate of 91.77 ± 0.279%. The micromorphology of the PBACS-TPP-Pur-NPs exhibited better physical properties. However, PBACS-PBA-Pur-NPs demonstrated a faster in vitro release and more significant in vitro anti-inflammatory effects. Pharmacokinetically, the AUC 0-24 , T max , and C max of PBACS-PBA-Pur-NPs were 3.485, 2.117, and 3.339 times higher, respectively, than those of Pur. The AUC 0-24 , T max , and C max of PBACS-TPP-Pur-NPs were 2.41, 1.33, and 2.03 times higher, respectively, than those of Pur. Molecular simulation revealed that the binding energy of PBACS-PBA-Pur -NPs was approximately -4.34 kcal/mol and that of PBACS-TPP-Pur-NPs was even lower, approximately -5.93 kcal/mol, suggesting that the NPs prepared with TPP are more densely packed than those designed with PBA, resulting in slower and reduced drug release. Conclusion The NPs constructed in this study effectively reduced inflammatory factors at the disease site, providing a theoretical and experimental basis for the application of nano drugs in inflammatory disease models. In addition, the molecular docking study of the two NPs offered insights into the relationship between the release and structure of subsequent nano drugs.
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ACS Applied Materials & Interfaces
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2024
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IF 8.3
Yongju He,Meiru Zhang,Xiyu Gong,Xiaoxuan Liu,Fangfang Zhou,Binbin Yang
Oxidative stress (OS) is a major mediator of secondary brain injury following intracerebral hemorrhage (ICH). Thus, antioxidant therapy is emerging as an attractive strategy to combat ICH. To achieve both reactive oxygen species (ROS) scavenging ability and on-demand drug release ability, we constructed a novel polydopamine (PDA)-coated diselenide-bridged mesoporous silica nanoparticle (DSeMSN) drug delivery system (PDA-DSeMSN). Edaravone (Eda) was blocked in the pores of DSeMSN by covering the pores with PDA as a gatekeeper. The drug maintained nearly “zero release” before reaching the lesion site, while in the ROS-enriched circumstances, the PDA shell went through degradation and the doped diselenide bonds broke up, triggering the disintegration of nanoparticles and leading to Eda release. Interestingly, the ROS-degradable property of the PDA shell and diselenide bond endowed the system with enhanced ROS-eliminating capacity. The synergistic effect of ROS-responsive drug delivery and ROS-scavenging PDA-DSeMSN showed efficient antioxidative and mitochondria protective performance without apparent toxicity in vitro. Importantly, PDA-DSeMSN@Eda through intravenous administration specifically accumulated in perihematomal sites and demonstrated robust neuroprotection in an ICH mouse model through antioxidative and antiapoptotic effects with high biological safety. Thus, the PDA-DSeMSN platform holds tremendous potential as an excellent carrier for on-demand delivery of drugs and provides a new and effective strategy for the clinical treatment of ICH.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Mingming Sun,Qiuying Wang,Ting Li,Wenzhu Wang,Zihan Li,Yufei Ji,Shuangyue Zhang,Yan Li,Wenshuai Liu,Yan Yu
Pressure ulcers (PUs) have emerged as a significant burden on both individuals and society. Effective treatment of PUs is a significant clinical challenge due to the compromised tissue microenvironment characterized by extracellular matrix (ECM) depletion, increased levels of reactive oxygen species (ROS), excessive inflammation and impaired angiogenesis. To this end, we have developed a glucomannan hydrogel (GM-P gel ) that mimics the skin's extracellular matrix to accelerate wound healing by regulating chronic inflammation in the PUs. This hydrogel not only faithfully replicates the components and nanofibrous architecture of ECM-like glycoproteins but also exhibits remarkable capabilities in enhancing neovascularization, scavenging ROS, and promoting macrophage polarization toward the M2 phenotype. In summary, this ECM-mimetic multifunctional hydrogel emerges as a promising dressing with diverse functionalities, capable of reshaping the compromised tissue environment without the need for additional drugs, exogenous cytokines, or cells. This presents a compelling and effective strategy for the repair and regeneration of chronic cutaneous wounds.
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CELLULAR SIGNALLING
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2024
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IF 4.4
Ziheng Yuan,Genfa Yi,Run Ma,Zhuo Wang,Jihong Hu,Wei Zhao,Ying Hu
Background Aldehyde oxidase 1 (AOX1) is associated with various pathophysiological processes, including cancer. Specifically, AOX1 has been demonstrated to have a close relationship with the progression of certain cancers. However, the expression, function, and mechanisms of action of AOX1 in gallbladder cancer (GBC) remain unclear. Methods Utilizing immunohistochemistry, the study quantified the prevalence of AOX1 within tissues of gallbladder carcinoma and those of the surrounding non-cancerous regions. In vitro assays using gallbladder carcinoma cell lines with modulated AOX1 expression levels were performed to assess the protein's role in cell proliferation, migration, and invasion. Furthermore, flow cytometry techniques were harnessed to determine the influence of AOX1 on the content of reactive oxygen species (ROS) in these cells. Additionally, the expression of epithelial-mesenchymal transition (EMT) markers and the Wnt/β-catenin signaling pathway markersin cells with varied AOX1 expression, detected through Western blot analyses. An in vivo xenograft model involving athymic mice was implemented to explore the influence of AOX1 on gallbladder tumor growth, with Western blot analysis applied to measure EMT marker expression in the resulting tumours. Results Elevated AOX1 protein levels have been observed in gallbladder carcinoma tissues, with such upregulation linked to a negative prognostic outlook for patients. In vitro analyses demonstrate that enhanced AOX1 expression facilitates gallbladder carcinoma cell proliferation, migration, and invasion, while AOX1 suppression yields an inhibitory effect on these cellular behaviors. Western blot results reveal an inverse relationship between AOX1 and E-cadherin levels, yet was positively correlation with N-cadherin, Vimentin, and Snail within both gallbladder cancer cells and in vivo xenograft tumours. Further mechanistic investigation indicates that AOX1 elevation augments reactive oxygen species (ROS) production and initiates the Wnt/β-catenin signaling pathway in these cells. The application of N -acetylcysteine (NAC) and/or KY1797K attenuates the proliferative, migratory, and invasive enhancements imparted by AOX1 overexpression and reinforces these effects when AOX1 is silenced—achieved through ROS mitigation and the obstruction of the Wnt/β-catenin pathway. In vivo studies corroborate these findings, showing AOX1 overexpression to amplify xenograft tumor growth and mesenchymal marker expression, whereas AOX1 interference did the opposite. Conclusions The study indicates that AOX1 functions as a carcinogenic factor in gallbladder carcinoma, enhancing cell proliferation, migration, invasion, and the EMT. These effects are driven by the activation of the Wnt/β-catenin pathway mediated by reactive oxygen species (ROS). Therefore,AOX1 presents potential as a valuable prognostic and diagnostic marker as well as a target for therapeutic intervention in the gallbladder cancer.
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MATERIALS & DESIGN
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2024
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IF 7.6
Pei Gong,Lulu Ren,Xinghui Gao,Jie Long,Weidong Tian,Min He
Local oxidative stress induced by surgical trauma has been recognized as one of pathogenesis for postsurgical adhesion tissue formation. Herein, tannic acid (TA) based metal-phenolic networks (MPNs) was assembled via chelating with Fe 3+ , and acted as a novel bio-filler for nanofibrous polycaprolactone (PCL) barrier membrane to endow it with reactive oxygen species (ROS) scavenging capacity. By chelating with Fe 3+ , the release of TA could last for more than 20 days, rendering the membrane with continuous ROS scavenging capacity. The modified membrane could effectively inhibit fibroblasts adhesion and proliferation, as well as immune cells recruitment, infiltration, and expression of pro-inflammatory cytokines. Consequently, a complete prevention of peritoneal adhesion formation was obtained in a rat model of sidewall defect-cecum abrasion, far better than commercial Poly lactic acid (PLA) membrane. Systematic biological mechanism investigations revealed that the enhanced anti-adhesion function was mainly ascribed to its robust ROS scavenging capacity, through which the PI3K-Akt signaling pathway was blocked, leading to repress of downstream NF-κB-TGFβ1-SMAD signaling pathway, finally inhibiting the bioactivity of fibroblasts and immune cells. This work provided a new strategy for the design of advanced barrier membrane, demonstrated its efficacy and mechanism on preventing postoperative adhesion, holding great promise for future clinical application.
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Biomaterials Advances
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2024
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IF 5.5
Jing Wang,Yue Wu,Huishan Li,Wenjue Kang,Wenhao Li,Shijia Fu
Nano hydroxyapatite (nHA) has been acknowledged for its inhibition efficiency on tumor cells and its excellent biocompatibility for normal tissue and cells. However, the low inhibitory efficiency of tumor cells and the ambiguous inhibitory mechanism limited its further application. In this work, four kinds of nHA with different sizes was prepared, and the one with the highest inhibition efficiency on 4T1 cells was screened as a substrate for developing the nanoparticles coated with polydopamine (PDA) coating, which was named nHA-PDA. Both in vivo and in vitro experiments were employed, and the results showed significantly higher inhibitory activity against 4T1 cells and 4T1-bared tumors by nHA-PDA. Further investigation revealed that the oxidative stress induced by PDA results in a large Reactive Oxygen Species (ROS) accumulation, thus triggering the mitochondria-dependent apoptosis pathway ROS-JNK/MAPK and inducing the cascade reaction of inhibiting the anti-apoptosis protein-Bcl-2 expression and activating the expression of the critical genes in apoptosis signaling pathway (caspase 3 and caspase 9). Besides, the significant increase of intracellular [Ca 2+ ] may also be an essential reason for the damage of mitochondria, eventually leading to apoptosis.
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Acta Biomaterialia
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2024
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IF 9.4
Xinyue He,Lianghong Peng,Liming Zhou,Huiling Liu,Yifan Hao,Yuhan Li,Zijin lv,Baohui Zeng,Xinmin Guo,Rui Guo
Diabetic ulcers are one of the common complications in diabetic patients. Delayed wound healing is associated with persistent pro-inflammatory M1 polarization, reduced angiogenesis and increased reactive oxygen species (ROS) in the microenvironment. Wound healing consists of multiple phases and therefore requires treatment tailored to each phase. In this study, a biphasic drug-releasing microneedle (MN) was fabricated to achieve early ROS scavenging and late accelerated angiogenesis to promote wound healing. Vascular endothelial growth factor (VEGF) was first encapsulated in methacryloylated sulfonated chitosan (SCSMA) microspheres (V@MP), and then V@MP was loaded into hyaluronic acid (HA) microneedles along with cerium dioxide nanoparticles (CONPs). Rapid dissolution of HA rapidly releases the CONPs to clear ROS, whereas the V@MP stays in the wound. SCSMA slow degradation prolongs the release of VEGF, thereby promoting angiogenesis. In vitro and in vivo studies have shown that this biphasic drug-releasing smart microneedle improves cell proliferation and migration, effectively scavenges ROS, promotes angiogenesis and tissue regeneration, and synergistically promotes M2 macrophage polarization. It provides a new delivery mode for nano-enzymes and growth factors that could be multifunctional and synergistic in the treatment of diabetic ulcers. Statement of Significance In our study, we present a microneedle (V@MP/C@MN) that can release drugs biphasically, which showed good repair ability in diabetic ulcer model. Large amounts of CONPs were rapidly released to alleviate oxidative stress during the inflammation of the wound, and V@MP stayed in the wound for a long period of time to release VEGF and promote angiogenesis in the late stage of wound healing. The results indicated that V@MP/C@MN could promote cell proliferation and migration, effectively scavenge ROS, promote angiogenesis and tissue regeneration, and synergistically promote M2 macrophage polarization, which could play a multifunctional and synergistic role in the treatment of diabetic ulcers.
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ACS Applied Nano Materials
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2024
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IF 5.3
Fanqi Meng,Lei Chen,Haoran Chen,Meili Shen,Guangyi Wang,Yulei Chang
Combined phototherapy with other therapeutic strategies can improve the therapeutic outcomes of tumors and reduce the side effects. However, shaping multiple modalities for combination therapy remains challenging. Herein, multiple stimuli-responsive drug-loaded micelles are presented, which are self-assembled from cypate-conjugated pH-sensitive poly(ethylene glycol)–poly(2-(diisopropylamino) ethyl methacrylate)–poly(2-aminoethyl methacrylate hydrochloride) and redox-responsive poly(glycidyl methacrylate)–poly(propylene sulfide) copolymer and loaded with chemo agents doxorubicin (DOX) and sorafenib (SRF, also a ferroptosis inducer) for enhanced tumor therapy. The DOX and SRF chemo drugs were encapsulated into the hydrophobic core of PPS and PDPA to enable multiple stimuli-responsive controlled drug delivery. In vivo and in vitro experiments are carried out to investigate the potential application for controlled drug release and systemic chemo-phototherapy. This study highlights the rational design of cypate-based drug-loaded micelles, offering multiple stimuli-responsive drug releases and synergistic photo-, ferro-, and chemotherapy in colorectal cancer.
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FARADAY DISCUSSIONS
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2016
·Vol. 196
·335-350
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IF 3.544
Jun Wang,Yinglong Wu,Fang Zeng,Shuailing Huang,Shuizhu Wu
Fluorophores with aggregation-induced emission (AIE) characteristics are attractive and versatile tools for both chemical sensing and biological imaging. Herein, we designed and synthesized a fluorescent light-up system CTPE-Tau with enhanced cellular uptake ability. The system possesses several advantages, such as a large Stokes shift, low cytotoxicity, and good photostability. Also, it has been successfully utilized to track esterase-activated release of taurine and to scavenge intracellular ROS, and shows great potential for trackable visualized therapy.
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ACS Applied Materials & Interfaces
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2020
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IF 8.758
Weiwei Zhao,Hua Wang,Ying Han,Haimang Wang,Yulong Sun,Hongyu Zhang
Osteoarthritis (OA) is a chronic joint disease and its progression and pathogenesis are highly associated with the significant increase of joint friction and overproduction of reactive oxygen species (ROS) in inflammation. Combination of ROS elimination and lubrication enhancement may provide a novel strategy for the treatment of OA. In the present study, a pure biomaterial and nondrug system P(DMA-co-MPC), synthesized via free radical copolymerization, was designed and developed for the first time using 2-methacryloxyethyl phosphorylcholine (MPC) as a bioinspired lubricant and N-(3,4-dihydroxyphenethyl)methacrylamide (DMA) as an ROS scavenger. Our results showed that the P(DMA-co-MPC) aggregates could efficiently eliminate the ROS radicals and provide good lubrication property by adjusting the molar ratio of DMA and MPC in the copolymer. It is attributed to the antioxidant function of the hydroquinone moiety in DMA and the hydration lubrication effect of the zwitterionic phosphocholine group in MPC. Furthermore, the in vitro experiments demonstrated that the P(DMA-co-MPC) showed good biocompatibility with MC3T3-E1 cells and intracellular anti-inflammatory property by inhibiting the production of ROS and regulating the expression levels of pro-inflammatory cytokines, pain-related gene, anabolic genes, and catabolic genes. In conclusion, the drug-free P(DMA-co-MPC) aggregates developed herein can achieve dual functions of lubrication enhancement and anti-inflammatory effect and thus they may be representative as promising candidates for the treatment of OA.
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Scientific Reports
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2024
·Vol. 14
·期 1
·1-15
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IF 3.8
Wang Yan,Wang Shasha,Ma Chenchen,Qi Weiwei,Lv Jing,Zhang Mengqi,Wang Shibo,Wang Rui,Lu Yangyang,Qiu Wensheng
Gastric cancer (GC) is the most common malignant tumor of the gastrointestinal tract and currently has a poor clinical outcome. Turmeric’s rhizome contains a polyphenolic component called curcumin (Cur), which has been demonstrated to inhibit a variety of tumor cells, such as pancreatic, colon, lung and gastric cancers. However, it remains to be elucidated how Cur functions in GC and what molecular processes underlie it. Here, Cur showed a stronger inhibitory effect on GC cells AGS and HGC27. In addition, Cur’s inhibition of GC cells growth was accompanied by increased ROS production, triggering of the Keap1-Nrf2 signaling pathway, and increased transcription of its downstream antioxidant genes HO-1, GCLM, and NQO1. However, when a ROS scavenger NAC was used, the inhibitory effect of Cur on GC cells was reversed. Nuclear factor erythroid 2-related factor 2 (Nrf2) is overexpressed or activated in cancers to shield cancer cells from oxidative damage by responding to oxidative stress (OS). Cur has been found to act as an activator of Nrf2. Notably, compared with Nrf2 knockdown and Cur alone, the combination of the two dramatically increased Cur-induced ROS overaccumulation and inhibition of GC cells proliferation, migration, and invasive abilities. Consistent with in vitro experiments, Cur combined with Nrf2 knockdown significantly inhibited tumor growth in nude mice transplanted with AGS cells. Therefore, we concluded that Nrf2 depletion enhanced Cur therapy effect in GC by inducing the excessive accumulation of ROS, indicating that this is a promising treatment strategy.
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JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-18
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IF 10.6
Yin Mingjing,Lei Doudou,Liu Yalan,Qin Tao,Gao Huyang,Lv Wenquan,Liu Qianyue,Qin Lian,Jin Weiqian,Chen Yin,Liang Hao,Wang Bailei,Gao Ming,Zhang Jianfeng,Lu Junyu
Acute lung injury (ALI) is a life threatening disease in critically ill patients, and characterized by excessive reactive oxygen species (ROS) and inflammatory factors levels in the lung. Multiple evidences suggest that nanozyme with diversified catalytic capabilities plays a vital role in this fatal lung injury. At present, we developed a novel class of polydopamine (PDA) coated cerium dioxide (CeO 2 ) nanozyme (Ce@P) that acts as the potent ROS scavenger for scavenging intracellular ROS and suppressing inflammatory responses against ALI. Herein, we aimed to identify that Ce@P combining with NIR irradiation could further strengthen its ROS scavenging capacity. Specifically, NIR triggered Ce@P exhibited the most potent antioxidant and anti-inflammatory behaviors in lipopolysaccharide (LPS) induced macrophages through decreasing the intracellular ROS levels, down-regulating the levels of TNF-α, IL-1β and IL-6, up-regulating the level of antioxidant cytokine (SOD-2), inducing M2 directional polarization (CD206 up-regulation), and increasing the expression level of HSP70. Besides, we performed intravenous (IV) injection of Ce@P in LPS induced ALI rat model, and found that it significantly accumulated in the lung tissue for 6 h after injection. It was also observed that Ce@P + NIR presented the superior behaviors of decreasing lung inflammation, alleviating diffuse alveolar damage, as well as promoting lung tissue repair. All in all, it has developed the strategy of using Ce@P combining with NIR irradiation for the synergistic enhanced treatment of ALI, which can serve as a promising therapeutic strategy for the clinical treatment of ROS derived diseases as well.
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