Redox Biology
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2026
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IF 16.2
Jiani Gao,Ke Zhou,Yijiu Ren,Fengjing Yang,Minjue Shan,Yubing Fang,Changbo Sun,Weili Han,Chang Chen,Xuefei Hu
Transfusion-related acute lung injury (TRALI) remains a life-threatening complication of blood transfusion, yet the macrophage-neutrophil-NETosis inflammatory amplification mechanism and effective interventions are still incompletely defined. Here, we examined a CD36/Fyn-CXCL-related axis in TRALI and evaluated a ROS-responsive platelet extracellular vesicle biomimetic nanosystem (PEV@SP@EG) as a targeted delivery strategy. In a murine TRALI model, exploratory single-cell transcriptomic analysis showed immune-cell remodeling and linked CD36 expression to M1-like macrophage features. CD36 knockdown or pharmacological inhibition of Fyn/NF-kappaB reduced M1 polarization markers, CXCL production, and ROS generation. Conditioned medium from CD36-overexpressing BMDMs promoted neutrophil migration and NETosis, whereas CXCL-CXCR2 blockade or CD36/Fyn inhibition weakened these responses. PEV@SP@EG showed ROS-triggered drug release and preferential lung enrichment. In vivo , PEV@SP@EG attenuated CD36/Fyn-NF-kappaB-CXCL-related inflammatory signaling, NET formation, and oxidative stress in TRALI lung tissue, with concomitant improvement in lung architecture and gas exchange. These findings support a role for macrophage CD36/Fyn signaling in TRALI-associated macrophage-neutrophil inflammatory crosstalk and suggest that PEV@SP@EG may provide a targeted nanotherapeutic delivery platform for TRALI intervention.
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Parasites & Vectors
·
2025
·Vol. 18
·期 1
·1-22
·
IF 3.5
Ji Hongyan,Huang Yutao,Tian Jingxuan,Bo Ruonan,Heng Xin,Yang Junyi,Huang Yifan,Wang Xiangyu,Tan Qingfeng,Gao Hua,Chen Linwei,Chen Jing
Background Chrysosplenetin (CHR), a polymethoxy flavonol co-occurring with artemisinin (ART) in Artemisia annua L., reverses ART resistance in Plasmodium berghei K173 potentially by downregulating intestinal P-glycoprotein (P-gp, encoded by Mdr1a ) expression. In the present study, we further elaborated on the mechanism by comparing differences in antimalarial activity and resistance-associated molecular expression profiles between ART alone and combination therapy in blood and tissues of Mdr1a wild-type (WT) and knockout (KO) mice infected with either sensitive or resistant malarial parasites. Methods We evaluated the effects of monotherapy and combination therapy in WT and KO mice infected with sensitive and resistant P. berghei K173 strains. The mRNA expressions of multi-resistance proteins (Mrp1, 2, 4, 5) and breast cancer resistance proteins (Bcrp) were detected. Hemoglobin levels, mRNA expressions of cytokines including tumor necrosis factor-α (IFN-α), interferon-α (IFN-α), and interleukin (IL-1β) in blood and tissues, and redox balance (ROS/GSH levels), as well as gene or protein expression of signaling pathway (PI3K/AKT-mTOR and MAPK) were investigated. Results In drug-resistant mice, combination therapy maintained the highest survival (100%) and inhibition (30%) rates and the lowest parasitaemia percentage (approximately 20.0%), irrespective of Mdr1a gene status. Furthermore, combination reshaped the spatial and ART resistance-phenotypic disparities in Mrps and Bcrp mRNA expressions (with a fold change ranging from 1.35 to 38.03), ROS/GSH balance (ranging from 1.02-fold to 10.18-fold), hemoglobin levels (ranging from 1.04-fold to 1.20-fold), and cytokine profiles (ranging from 1.14-fold to 37.79-fold) induced by ART alone, which were partially dysregulated by Mdr1a deficiency. Monotherapy and combination exert oppositely regulatory effects on the PI3K/AKT-mTOR pathway in a tissue-, Mdr1a genotype-, and parasite sensitivity/resistance-dependent manner (ranging from 1.52-fold to 84.00-fold). Specifically, CHR reversed ART-induced changes via PI3K/AKT protein inhibition (ranging from 1.20-fold to 63.00-fold), which was contingent on P-gp functionality. Finally, mitogen-activated protein kinase (MAPK) pathway was involved in the antagonistic regulation between ART alone and combination therapy in a P-gp-independent manner (ranging from 1.39-fold to 16.69-fold). Conclusions The efflux pump function of P-gp is probably not a critical factor in the mechanism by which CHR reverses ART resistance. Instead, CHR acts as a homeostasis stabilizer with dual functions: it disrupts Plasmodium berghei K173 resistance to ART driven by both ABC transporters and the heme-ROS/GSH axis, in which the non-transport function of P-gp on ART is involved. Graphical
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Journal of Agriculture and Food Research
·
2026
·
IF 7.2
Yizhu Chen,Yi Liu,Yurong Fang,Huixue Huang,Zhihong Long,Bomi Ryu,Haisheng Xie,Zhong-Ji Qian
Age related macular degeneration (AMD) is one of the main causes of blindness in. elderly patients, and its treatment methods include intraocular injection and oral. administration, requiring long-term treatment and suboptimal efficacy. Tilapia skin-derived oligopeptides, characterized by high safety and bioactivity, emerge as a promising source of functional food ingredients. Here, we investigated the protective mechanism of TBP-1 (Ser-Val-Val-Ala-Ile), a pentapeptide isolated from tilapia skin, against hypoxia-induced damage in retinal pigment epithelial (ARPE-19) cells and angiogenesis in human umbilical vein endothelial cells (HUVECs). In the functional evaluation, TBP-1 notably attenuated ROS overproduction in CoCl 2 -induced ARPE-19 cells, simultaneously suppressing the stabilization of hypoxia-inducible factor-1α (HIF-1α), which was associated with reduced vascular endothelial growth factor (VEGF) transcription, diminished inflammatory factor levels, and restoration of normal autophagic flux. To validate the ROS-dependent nature of this regulatory pathway, we performed a rescue experiment using N-acetylcysteine (NAC), a well-characterized ROS scavenger. In HUVECs activated by VEGF, TBP-1 decreased the phosphorylation of VEGFR-2 and dampened the activation of the MAPK signaling pathway, resulting in dose-dependent inhibition of cell migration, invasion, and the formation of capillary-like tubular structures. Molecular docking and quantum chemical analyses suggested that the bioactivity of TBP-1 may rely on the electron-donating property of the Ser residue and hydrophobic interactions mediated by Ile, both of which are critical for its ROS scavenging ability and predicted interaction with HIF-1α. Collectively, these findings suggest that TBP-1 is a multi-target functional food supplement for preventing AMD by targeting the ROS/HIF-1α/VEGF axis, providing a theoretical basis for the high-value utilization of tilapia skin.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2022
·
IF 8.025
Qiang Chen,Chunjing Guo,Xiudi Zhou,Yanguo Su,Huimin Guo,Min Cao,Jing Li,Yue Zhang,Weiyi Zhao,Xin Gao,Shuqi Mi,Daquan Chen
Currently, very limited therapeutic approaches are available for the drug treatment of atherosclerosis(AS). H 2 S-donor is becoming a common trend in much life-threatening research. Several studies have documented that H 2 S-lyase is predominantly present in endothelial cells. N-Acetylneuraminic acid (SA), natural carbohydrate, binds specifically to the E -selectin receptor of endothelial cells. Meanwhile, recent studies related to Chondroitin sulfate have excellent target binding ability with CD44 receptor. We conjecture that the N-Acetylneuraminic acid and Chondroitin sulfate modified nanomicelles not only enhances the accumulation of the drug but also cleaves the H 2 S donor in the lesion, thus one stone two birds. Given these findings, we synthesized two kinds of nanoparticles, Carrier I (SCCF) and Carrier II (SCTM), for atherosclerosis to validate our guesses. Initially, S-allyl-L-cysteine and 4-methoxyphenylthiourea were used as H 2 S donors for SCCF and SCTM, respectively. After the introduction of ROS-sensitive groups. Then, micelles with N-Acetylneuraminic acid and Chondroitin sulfate were prepared to load rapamycin(RAP). Further, in atherosclerosis Oil Red O staining (ORO) results confirmed remarkable treatment effect with [email protected] and [email protected] Thus, we conclude that the effect of dual-targeting nanomicelles with ROS-sensitive H 2 S donor based on N-Acetylneuraminic acid and Chondroitin sulfate will have a better role in atherosclerosis.
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PHARMACOLOGICAL RESEARCH
·
2019
·
IF 5.574
Jin-Feng Teng,Da-Lian Qin,Qi-Bing Mei,Wen-Qiao Qiu,Rong Pan,Rui Xiong,Ya Zhao,Betty Yuen-Kwan Law,Vincent Kam-Wai Wong,Yong Tang,Chong-Lin Yu,Feng Zhang,Jian-Ming Wu,An-Guo Wu
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Our previous studies have proven that Trillium tschonoskii Maxim. (TTM), a traditional Chinese medicine , possesses potent anti-tumor effect. However, the detailed components and molecular mechanism of TTM in anti-NSCLC are still unknown. In the present experiment, polyphyllin VI (PPVI) was successfully isolated from TTM with guidance of the anti-proliferative effect in A549 cells, and the cell death of PPVI treated A549 and H1299 cells was closely linked with the increased intracellular ROS levels. In addition, PPVI induced apoptosis by promoting the protein expression of Bax/Bcl2, caspase-3 and caspase-9, and activated autophagy by improving LC3 II conversion and GFP-LC3 puncta formation in A549 and H1299 cells. The mechanism study found that the activity of mTOR which regulates cell growth, proliferation and autophagy was significantly suppressed by PPVI. Accordingly, the PI3K/AKT and MEK/ERK pathways positively regulating mTOR were inhibited, and AMPK negatively regulating mTOR was activated. In addition, the downstream of mTOR, ULK1 at Ser 757 which downregulates autophagy was inhibited by PPVI. The apoptotic cell death induced by PPVI was confirmed, and it was significantly suppressed by the overexpression of AKT, ERK and mTOR, and the induced autophagic cell death which was depended on the Atg7 was decreased by the inhibitors, such as LY294002 (LY), Bafilomycin A1 (Baf), Compound C (CC) and SBI-0206965 (SBI). Furthermore, the mTOR signaling pathway was regulated by the increased ROS as the initial signal in A549 and H1299 cells. Finally, the anti-tumor growth activity of PPVI in vivo was validated in A549 bearing athymic nude mice . Taken together, our data have firstly demonstrated that PPVI is the main component in TTM that exerts the anti-proliferative effect by inducing apoptotic and autophagic cell death in NSCLC via the ROS-triggered mTOR signaling pathway, and PPVI may be a promising candidate for the treatment of NSCLC in future.
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高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2017
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IF 2.466
Menglu Zhou,Shuying Shen,Xin Zhao,Xingguo Gong
Autophagy has attracted a great deal of interest in tumour therapy research in recent years. However, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, on autophagy remains poorly understood in human lung cells. In the present study, we have investigated the anticancer effects of luteoloside on non-small cell lung cancer (NSCLC) cells and demonstrated that luteoloside effectively inhibited cancer cell proliferation , inducing G 0 /G 1 phase arrest associated with reduced expression of CyclinE, CyclinD1 and CDK4; we further found that treatment with luteoloside did not strongly result in apoptotic cell death in NSCLC (A549 and H292) cells. Interestingly, luteoloside induced autophagy in lung cancer cells, which was correlated with the formation of autophagic vacuoles, breakdown of p62, and the overexpression of Beclin-1 and LC3-II, but not in a human bronchial epithelial cell line (BEAS-2B). Notably, pretreatment of cancer cells with 3-MA, an autophagy inhibitor, protected against autophagy and promoted cell viability but not apoptosis. To further clarify whether luteoloside-induced autophagy depended on the PI3K/AKT/mTOR/p70S6K signalling pathway , a major autophagy-suppressive cascade, cells were treated with a combination of AKT inhibitor (LY294002) and mTOR inhibitor (Rap). These results demonstrated that luteoloside induced autophagy in lung cancer cell lines by inhibiting the pathway at p -Akt (Ser473), p -mTOR and p-p70S6K (Thr389). Moreover, we observed that luteoloside-induced cell autophagy was correlated with production of reactive oxygen species (ROS). NAC-mediated protection against ROS clearly implicated ROS in the activation of autophagy and cell death. In addition, the results showed that ROS served as an upstream effector of the PI3K/AKT/mTOR/p70S6K pathway. Taken together, the present study provides new insights into the molecular mechanisms underlying luteoloside-mediated cell death in NSCLC cells and supports luteoloside as a potential anti-cancer agent for targeting NSCLC through the induction of autophagy, inhibition of proliferation and PI3K/AKT/mTOR/p70S6K signalling.
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高影响因子
JOURNAL OF MATERIALS SCIENCE & TECHNOLOGY
·
2024
·
IF 11.2
Rui Zhang,Zhiling Chen,Yi Li,Delun Chen,Tao Wang,Bingrong Wang,Qionglin Zhou,Shaowen Cheng,Dan Xu,Xiaohong Wang,Lina Niu,Jinchun Tu,Qiang Wu
The use of zinc oxide (ZnO) photosensitizers (PSs)-mediated photodynamic therapy (PDT) against bacterial wound infections is greatly restricted by diminished photocatalytic efficiency caused by the rapid recombination of photogenerated electrons and holes. In this work, ZnO PSs with a Ni-doped/oxygen vacancy and a protective carbon shell were successfully synthesized by calcinating a Ni-doping zeolitic imidazolate framework-8 precursor. The double-defect structure and the carbon-based substrates significantly promoted the efficiency of photogenerated electron–hole pair separation, meanwhile, the optimal proportion of 3% Ni doping endows it with the best photocatalytic performance as elucidated by photodegradation assays of methylene blue (MB) and density functional theory (DFT) calculations, reinforcing the generation of reactive oxygen species (ROS) by ZnO and showing obvious advantages in antibacterial properties. As the ROS damage that facilitates the photogenerated electron transfer underwent localized accumulation, the PSs disturbed the bacterial membrane integrity and caused bacterial ATP synthesis inhibition, further leading to bacterial lysis and promoting bacterial deaths. Additionally, the PSs showed outstanding efficacy in eradicating bacterial biofilms. Simultaneously, the significantly enhanced PDT antibacterial performance of the PSs in vivo could initiate wound tissue repair and trigger anti-inflammatory reactions by significantly regulating the expression levels of regeneration- and inflammation-related genes or proteins. Furthermore, the PSs consistently exhibited favorable compatibility both in vitro and in vivo . In summary, this study offers evidence of the remarkably efficient and biologically safe performance of Ni-ZnO@C PSs, with antibacterial properties advancing wound healing, both in controlled laboratory environments and living organisms, further underscoring their substantial potential for biomedical applications.
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BIOCHEMICAL PHARMACOLOGY
·
2022
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IF 6.1
Xiaodong Sun,Tengjiao Fan,Guohui Sun,Yue Zhou,Yaxin Huang,Na Zhang,Lijiao Zhao,Rugang Zhong,Yongzhen Peng
Chloroethylnitrosoureas (CENUs) exert antitumor activity via producing dG-dC interstrand crosslinks (ICLs). However, tumor resistance make it necessary to find novel strategies to improve the therapeutic effect of CENUs. 2-Deoxy-D-glucose (2-DG) is a well-known glycolytic inhibitor, which can reprogram tumor energy metabolism closely related to tumor resistance. Here, we investigated the chemosensitization effect of 2-DG on l,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) against glioblastoma cells and the underlying mechanisms. We found that 2-DG significantly increased the inhibitory effects of BCNU on tumor cells compared with BCNU alone, while 2-DG showed no obvious enhancing effect on the BCNU-induced cytotoxicity for normal HaCaT and HA1800 cells. Proliferation, migration and invasion determinations presented the same trend as survival on tumor cells. 2-DG plus BCNU increased the energy deficiency through a more effective inhibition of glycolytic pathway. Notably, the combination of 2-DG and BCNU aggravated oxidative stress in glioblastoma cells, along with a significant decrease in glutathione (GSH) levels, and an increase in intracellular reactive oxygen species (ROS). Subsequently, we demonstrated that the combination treatment led to increased apoptosis via activating mitochondria and endoplasmic reticulum stress (ERS) related apoptosis pathways. Finally, we found that the dG-dC level was significantly increased after 2-DG pretreatment compared to BCNU alone by HPLC-ESI-MS/MS analysis. Finally, in vivo , 2-DG plus BCNU significantly suppressed tumor growth with lower side effects compared with BCNU alone in tumor-bearing mice. In summary, we proposed that 2-DG may have potential to increase the sensitivity of glioblastoma cells to BCNU by regulating glycolysis, ROS and ERS pathways in clinical setting.
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Biomaterials Science
·
2020
·Vol. 9
·期 1
·221-237
·
IF 6.183
Zhiqiang Zhang,Anning Li,Xingqi Min,Qunqun Zhang,Jun Yang,Guo Chen,Meijuan Zou,Wei Sun,Gang Cheng
Chemotherapy and surgery are commonly used clinical treatments for breast cancer. However, unsatisfactory therapeutic effects, unavoidable side effects, and the removal of breast tissue during surgery are still major obstacles to be overcome during breast-cancer treatment. To overcome the aforementioned issues, a biomimetic and thermosensitive hydrogel encapsulating reactive oxygen species (ROS)-sensitive tegafur (TF)-protoporphyrin IX (PpIX) heterodimers (TTP) was prepared aimed at the strategy of synergizing chemotherapy and photodynamic therapy. TF was grafted onto the photosensitizer PpIX through ROS-sensitive thioether bonds. Under 630 nm laser irradiation, the ROS concentration in tumors was increased to help drug release. The “on-demand” drug release maximized the therapeutic effects of TF and effectively reduced its toxicity. Particularly, the ROS concentration was increased, and it was expected that the tumor-cell-killing abilities of ROS could be exploited. A hydrogel formed from temperature-sensitive chitosan and silk sericin was selected as a drug carrier, which formed a drug reservoir intratumorally after intratumoral injection. Intratumoral injection gave the drug precise and long-term release behavior, which allowed for the clever avoidance of various physical and biological barriers in vivo. In vivo and in vitro studies prove that the use of this TTP hydrogel provides a new attempt to overcome the many difficulties related to breast-cancer treatment simultaneously, and this study opens up new paths for breast-cancer treatment.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Chuanxin Liu,Xiaobin Huang,Jiao Kong,Xuejiao Li,Yuming Wang,Fangfang Zhang,Jiajia Duan
Background Podophyllotoxin (PPT), a highly active compound extracted from the rhizome of Dysosma versipellis (DV), has been used as an effective anti-cancer drug clinically since the 1950s. It possesses various biological activities, including antiviral and antitumor effects. However, its clinical application is severely limited due to its hepatotoxicity, and the underlying mechanisms remain unclear. This study aims to elucidate the mechanisms of PPT-induced hepatotoxicity using tandem quality tag (TMT) based quantitative proteomics and phosphoproteomics, providing potential targets and directions for developing new therapeutic strategies to facilitate the safe and rational use of podophyllotoxin in clinical settings. Methods We employed a comprehensive assessment of PPT-induced hepatotoxicity based on the Toxicology Evidence Chain (TEC) concept, originally proposed by our research group in 2018. This approach involves a tiered search for evidence of Harmful Ingredients Evidence (HIE), Injury Phenotype Evidence (IPE), Adverse Outcomes Evidence (AOE), and Toxic Events Evidence (TEE) during the development of PPT-induced hepatotoxicity, thereby constructing a guiding toxicology evidence chain. Sprague-Dawley (SD) rats were administered 20 mg/kg PPT for 4 consecutive days (HIE). Indicators such as hepatic function, oxidative stress, inflammatory factors, as well as the histopathology of liver tissue were evaluated to assess liver damage and synthetic function (AOE). Proteomics and phosphoproteomics were conducted to systematically assess PPT-induced hepatotoxicity at the level of modified proteins and verify the molecular mechanisms of key molecular pathways (TEE1). Furthermore, in vitro THLE-2 cell models were used in conjunction with CCK8, immunofluorescence, and ELISA assays to validate cytotoxicity and its underlying mechanisms (TEE2). Results Our results showed that after 4 days of PPT administration at 20 mg/kg (HIE), serum levels of AST/ALT, TBA, TP, and ALB in SD rats were significantly increased ( P < 0.05), indicating severe liver damage. SOD and T-AOC levels were significantly decreased ( P < 0.05), suggesting an oxidative stress state. TNF-α levels were significantly elevated, while IL-10 and IL-3 levels were significantly reduced ( P < 0.05), indicating strong activation of the inflammatory response in the liver. Histopathological examination revealed liver sinusoidal congestion in the liver tissue (AOE). Omics analysis revealed that hepatotoxicity primarily affected the complement-pyroptosis and cGMP-PKG-autophagy pathways. Western blot (WB) and RT-qPCR results showed significant upregulation of complement-pyroptosis pathway proteins (C5a, C5aR, NLRP3) and cGMP-PKG-autophagy pathway proteins (PKG, mTOR) in the PPT group ( P < 0.05) (TEE1). In vitro cell experiments showed that PPT significantly reduced cell viability ( P < 0.05) and increased the expression of proteins associated with pyroptosis and autophagy pathways, including ROS, NLRP3, PKG, and mTOR ( P < 0.05) (TEE2). Conclusion PPT activates the complement system through the C5a/C5aR/ROS/NLRP3 pathway and induces the formation of inflammasomes, promoting pyroptosis. Simultaneously, PPT activates the cGMP-PKG pathway, inhibiting autophagy and further accelerating pyroptosis, ultimately leading to hepatotoxicity. In conclusion, this study comprehensively revealed the underlying mechanisms of PPT-induced hepatotoxicity using the TEC concept. This approach transforms fragmented toxicity indicators into systematic evidence of toxicity, presenting a hierarchical progression of toxicity evidence and avoiding data accumulation in natural drug toxicology. Our findings represent a significant breakthrough in the elucidation of the mechanisms of hepatotoxicity induced by podophyllotoxin.
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PHYTOMEDICINE
·
2023
·
IF 7.9
Xi Chen,Ning Zhu,Yajie Wu,Ye Zhang,Yuxuan Zhang,Kaiwen Jin,Zhiyi Zhou,Guang Chen,Jiabing Wang
Background Sorafenib (Sora), a multi-target tyrosine kinase inhibitor, is widely recognized as a standard chemotherapy treatment for advanced hepatocellular carcinoma (HCC). However, drug resistance mechanisms hinder its anticancer efficacy. Derived from Withania somnifera , Withaferin A (WA) exhibits remarkable anti-tumor properties as a natural bioactive compound. This study aimed to examine the mechanisms that underlie the impacts of Sora and WA co-treatment on HCC. Methods Cell proliferation was evaluated through colony formation and MTT assays. Flow cytometry was employed to determine cellular apoptosis and reactive oxygen species (ROS) levels. The evaluation of apoptosis-related protein levels, DNA damage, and endoplasmic reticulum stress was conducte utilizing IHC staining and western blotting. Moreover, the caspase inhibitor Z-VAD-FMK, ATF4 siRNA, ROS scavenger N-acetyl cysteine (NAC), and TrxR1 shRNA were used to elucidate the underlying signaling pathways. To validate the antitumor effects of Sora/WA co-treatment, in vivo experiments were ultimately executed using Huh7 xenografts. Results Sora/WA co-treatment demonstrated significant synergistic antitumor impacts both in vivo and in vitro . Mechanistically, the enhanced antitumor impact of Sora by WA was achieved through the inhibition of TrxR1 activity, resulting in ROS accumulation. Moreover, ROS generation induced the activation of DNA damage and endoplasmic reticulum (ER) stress pathways, eventually triggering cellular apoptosis. Pre-treatment with the antioxidant NAC significantly inhibited ROS generation, ER stress, DNA damage, and apoptosis induced by Sora/WA co-treatment. Additionally, the inhibition of ATF4 by small interfering RNA (siRNA) attenuated Sora/WA co-treatment-induced apoptosis. In vivo , Sora/WA co-treatment significantly suppressed tumor growth in HCC xenograft models and decreased TrxR1 activity in tumor tissues. Conclusion Our study suggests that WA synergistically enhances the antitumor effect of Sora, offering promising implications for evolving treatment approaches for HCC.
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CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Yanan Wang,Huichao Wei,Keyang Li,Liru Liu,Yingfei Zhu,Xinyuan Wang,Jiahui Yan,Liangmin Yu,Xuefeng Yan,Zhiyu He
Calcium overload in hepatocytes mediates the crosstalk and amplification loop with oxidative stress and severe inflammation that initiate pro-apoptotic and necrotic signaling pathways in acute liver injury (ALI). In this study, an N-acetylgalactosamine-modified amphiphilic dextran-silibinin conjugate (GalNAc-Dex-Sil) with ROS-sensitive phenylboronic acid (PBA) linkage was synthesized. The as-prepared amphiphilic polymer was self-assembled into GalNAc-Dex-Sil nanoparticles, which efficiently encapsulated the membrane-permeable calcium chelator BAPTA-AM (BA), achieving GalNAc-mediated hepatocyte-specific targeting and ROS-responsive release in injured hepatocytes through PBA cleavage. Accordingly, a single low-dose injection of formulation (BA: 150 μg·kg −1 ) significantly alleviated hepatocyte oxidative stress and inflammation, rescued dying hepatocytes, prevented further hepatocyte damage, and ultimately restored liver function in the ALI mouse model by 1) rapidly and effectively eliminating the overloaded calcium and scavenging excessive ROS via released BA to block the feed-forward vicious cycles of the cell damage, 2) inhibiting the inflammatory cascade by decreasing the expression of the key factor of the NF-κB/NLPR3 axis, 3) inhibiting the key branch of the mitochondrial apoptotic pathway (Cyt C/Bcl-2 family/caspase-3 axis) and death receptor pathway (TNFα/Caspase-8 axis), and 4) stabilizing hepatocyte membranes through the synergistic hepatoprotective effect of silibinin. Taken together, this formulation exhibited great potential as a potent and effective ALI treatment strategy.
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