ENVIRONMENTAL POLLUTION
·
2023
·
IF 8.9
Xiaojing Li,Qian Wu,Dan Chen,Yichen Bai,Yuhong Yang,Shiwen Xu
Cadmium (Cd) is a major contaminant in natural environments and exerts adverse effects on aquatic biota at low concentrations. Gill is as vital respiratory organ and may cause pollutants to enter fish during gas exchange. Baicalein (BAI), as a kind of flavonoids, possess antioxidant properties through inactivating free radicals. To confirm the potential effects and approaches of BAI addition in maintaining the gill stability, 90 common carps ( Cyprinus carpio L.) were selected and randomly divided into water environment exposure group (0.22 mg/L Cd) and/or feed added with 0.10 g/kg BAI for 30 days. The analysis of ion content in serum showed that Cd exposure disturbed ion homeostasis , and BAI could reduce serum Cd concentration. The histopathological results of gills showed that Cd exposure caused gill tissue lesions and structural damage, and BAI feeding effectively alleviated this damage. In addition, BAI could enhance antioxidant activity and activate Nrf2/HO-1 axis, thereby reducing oxidative stress and endoplasmic reticulum (ER) stress. Moreover, BAI lightened cytokine imbalance, inflammatory response, and necroptosis. Overall, the results indicated that BAI feeding could maintain gill homeostasis against Cd poisoning via the ROS/ER stress signaling. This trial revealed the properties of BAI resistance to metal Cd in aquaculture and partially elucidated its mechanism.
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ENVIRONMENTAL TOXICOLOGY
·
2023
·
IF 4.5
Yating Sheng,Chengpeng Zhang,Dandan Cai,Guangtao Xu,Shipiao Chen,Weijian Li,Jingjian Dong,Bin Shen,Jie Tang,Long Xu
We have previously found that a mixture exposure of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) and cadmium (Cd) causes kidney damage; however, the mechanism was not fully understood. The aryl hydrocarbon receptor (AhR) is a ligand–receptor transcription factor that plays an important role in the adaptive response or metabolic detoxification of environmental toxins. Thus, this study aimed to examine the role of AhR in kidney toxicity. BDE-47 (50 μM) or Cd (5 μM) exposure reduced cell viability in renal tubular epithelial cells (HKC), with a larger effect observed in co-treatment. The cell morphology presented pyroptotic changes, including swollen cells, large bubbles, and plasma membrane pore formation. The gene expressions of AhR, heat shock protein 90 (Hsp90), AhR nuclear translocator (ARNT), and cytochrome P450 1B1 (CYP1B1) were increased, while CYP1A1 was decreased. Reactive oxygen species (ROS) were generated, which was reduced by the AhR antagonist CH223191. The apoptosis, necrosis, and intracellular lactated hydrogenase (LDH) release was elevated, and this was attenuated by N-acetylcysteine (NAC). Furthermore, the pyroptosis pathway was activated with increased protein levels of cleaved-caspase-3 and gasdermin E N-terminal (GSDME-NT), while caspase-8, caspase-3, and GSDME were decreased. These effects were alleviated by NAC and CH223191. Our data demonstrate a combined effect of BDE-47 and Cd on nephrotoxicity by activating AhR to induce ROS contributing to GSDME-dependent pyroptosis, and retardation of the AhR pathway could reduce this toxicity.
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Journal of Materials Chemistry B
·
2017
·Vol. 5
·期 46
·9157-9164
·
IF 4.543
Long Xu,Mingying Zhao,Yidi Yang,Yan Liang,Changzhen Sun,Wenxia Gao,Sai Li,Bin He,Yuji Pu
Low molecular weight gels (LMWGs) have significant advantages in drug delivery such as high drug loading capacity, in situ delivery of drug to the lesion site, sustaining drug release with excellent bioavailability, and minimized side effects. Here, we synthesized a reactive oxygen species (ROS)-responsive gelator to prepare an injectable gel. An anticancer drug, doxorubicin hydrochloride (DOX), and a photosensitizer, Zn(II) phthalocyanine tetrasulfonic acid (ZnPCS4), were loaded into the gel for combined chemo-photodynamic therapy. The ROS-responsive gelator was characterized by proton nuclear magnetic resonance (1H NMR) and the morphology of gels was investigated by scanning electron microscopy (SEM). The rheological properties and destruction–recovery capability of both blank and drug-loaded gels were studied. The cytotoxicity of LMWGs against 3T3 fibroblasts and 4T1 breast cancer cells was tested. The in vitro drug release of both drugs was studied and the in vivo anticancer activities of DOX–ZnPCS4-coloaded LMWGs were investigated in tumor-bearing mice. The results revealed that the injectable ROS-responsive DOX–ZnPCS4-coloaded LMWGs exhibited excellent anti-tumor efficacy by a synergistic therapy.
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Journal of Fungi
·
2024
·Vol. 10
·期 11
·801
·
IF 4.2
Di Wang,Lingkui Meng,Haijue Zhang,Rong Liu,Yuhan Zhu,Xinyu Tan,Yan Wu,Qingchao Gao,Xueyan Ren,Qingjun Kong
Black spot, one of the major diseases of kiwifruit, is caused byAlternaria alternata. A comprehensive investigation into its pathogenicity mechanism is imperative in order to propose a targeted and effective control strategy. The effect of L-arginine on the pathogenicity ofA. alternataand the underlying mechanisms were investigated. The results showed that treatment with 5 mM L−1of L-arginine promoted spore germination and increased the colony diameter and lesion diameter ofA. alternatain vivo and in vitro, which were 23.1% and 9.3% higher than that of the control, respectively. Exogenous L-arginine treatment also induced endogenous L-arginine and nitric oxide (NO) accumulation by activating nitric oxide synthase (NOS), arginine decarboxylase (ADC) and ornithine decarboxylase (ODC). In addition, exogenous L-arginine triggered an increase in reactive oxygen species (ROS) levels by activating the activity and inducing gene expression upregulation of NADPH oxidase. The hydrogen peroxide (H2O2) and superoxide anion (O2.−) levels were 15.9% and 2.2 times higher, respectively, than in the control group on the second day of L-arginine treatment. Meanwhile, antioxidant enzyme activities and gene expression levels were enhanced, including superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), glutathione peroxidase (GPX), and glutathione reductase (GR). In addition, exogenous L-arginine stimulated cell wall-degrading enzymes in vivo and in vitro by activating gene expression. These results suggested that exogenous L-arginine promoted the pathogenicity ofA. alternataby inducing the accumulation of polyamines, NO, and ROS, and by activating systems of antioxidants and cell wall-degrading enzymes. The present study not only revealed the mechanism by which low concentrations of L-arginine increase the pathogenicity ofA. alternata, but also provided a theoretical basis for the exclusive and precise targeting ofA. alternatain kiwifruit.
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METABOLISM-CLINICAL AND EXPERIMENTAL
·
2025
·
IF 11.9
Chunmei Xiu,Lei Zhang,Chenxi Zhang,Yuannan Zhang,Xi Luo,Ziyi Zhang,Hangkai Zhao,Kaizhong Ji,Zhiyuan Chen,Guangxu He,Jianquan Chen
Aberrant increases in osteoclast formation and/or activity are the underlying cause of bone loss in a variety of osteolytic diseases. Fatty acid synthase (Fasn)-mediated de novo lipogenesis ( DNL ) is one of the major lipid metabolic pathways and has been shown to play critical roles in diverse physiological and pathological processes. However, little is known about its role in osteoclastogenesis. Here, we investigate the direct role of DNL in osteoclastogenesis and its therapeutic potential in osteolytic diseases. We found that Fasn expression and DNL levels are upregulated during receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Inhibition of Fasn by shRNA knockdown or its pharmacological inhibitors (ASC40 and trans-C75) impairs osteoclast differentiation in vitro . Mechanistically, pharmacological inhibition of Fasn suppresses RANKL-induced c-Fos/NFATc1 expression and thus osteoclastogenesis partly by disrupting STAT3 palmitoylation, while promoting ROS scavenging to impair mitogen-activated protein kinase (MAPK) signaling. Finally, the therapeutic potential of ASC40 for the treatment of osteolytic bone loss is tested in two mouse models of osteolytic diseases, i.e. ovariectomy (OVX)-induced osteoporosis and titanium nanoparticle-induced calvarial osteolysis. The results show that ASC40 significantly attenuates bone loss and osteoclastogenesis in both models. In conclusion, our results demonstrate that Fasn-mediated DNL is a novel positive regulator of osteoclastogenesis and may serve as a promising therapeutic target for the treatment of osteoclast-driven osteolytic bone diseases.
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Nano Research
·
2022
·Vol. 15
·期 9
·8214-8227
·
IF 10.269
Ding Yifan,Wang Huan,Wang Yunyun,Li Long,Ding Jiahui,Yuan Caiyan,Xu Tao,Xu Haoran,Xie Hui,Zhu Ning,Hu Xin,Fang Huang,Tan Songwei
Intervertebral disc degeneration (IDD) is closely related to inflammation and imbalance of synthesis/catabolism of extracellular matrix (ECM) in intervertebral disc (IVD). Considering this, luteolin (LUT), a kind of natural flavonoid with good anti-inflammatory effect and TGF-β1 (a gene that promotes the regeneration of ECM) plasmid was co-loaded and co-delivered to nucleus pulposus cells (NPCs). Reactive oxygen species (ROS) responsive cationic copolymer, poly(β-amino ester)-poly(ε-caprolactone) (PBC), with high plasmid DNA (pDNA) compression affinity was synthesized. It can self-assemble into nano-sized polyplexes (pDNA@PBC) with virus-inspired structure and function through which it can transfect pDNA into NPCs with very high efficiency and negligible cytotoxicity. LUT was encapsulated in the hydrophobic core of pDNA@PBC. The co-delivery system, LUT-pTGF-β1@PBC, could enhance the cellular uptake of NPCs and manifest excellent sustained drug release in IVD. Real time quantitative polymerase chain reaction (RT-qPCR) and Western blot experiments reveal that the co-delivery system could inhibit inflammation in NPCs and restore the balance of anabolism and catabolism in vitro by activating TGF/SMAD3 and inhibiting NF- k B/p65. Moreover, LUT-pTGF-β1@PBC retards IDD in vivo as detected by radiological and histological methods with good biosafety in rats. LUT-pTGF-β1@PBC may be a promising option for the treatment of IDD.
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Materials Today Bio
·
2025
·
IF 10.2
Weitong Sun,Bingbing Fan,Xiaohan Qin,Xin Zhang,Pengxia Zhang,Yu Zhang
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, driven by complex interactions between inflammatory pathways, gut microbiota dysbiosis, and tumor microenvironment remodeling. Conventional therapies, particularly single-target oral chemotherapeutics, are hindered by poor bioavailability, systemic toxicity, and drug resistance. To address these limitations, we engineered KGM-PTX/CSM microspheres, a dual-responsive drug delivery system leveraging the elevated reactive oxygen species (ROS) in CRC and β-mannanase overexpression in the colorectum. The system comprises ROS-sensitive prodrug micelles (PSM) encapsulated within konjac glucomannan (KGM). PSM micelles were synthesized by conjugating hydrophilic chitosan oligosaccharides (COS) with the hydrophobic anti-inflammatory agent mesalazine (MSL) via ROS-labile thioether bonds, followed by paclitaxel (PTX) encapsulation. Upon oral administration, KGM undergoes β-mannanase-triggered degradation in the colon, releasing PSM micelles that subsequently disintegrate in the ROS-rich tumor microenvironment, enabling spatiotemporally controlled drug release. In vitro studies demonstrated ROS-responsive drug liberation (91.2% cumulative release within 48 h) and enhanced cytotoxicity against PTX-resistant SW480/PTX cells (IC 50 : 9.33 μg/mL vs. 45.68 μg/mL for free PTX). Mechanistic investigations revealed synergistic interactions among the system’s components: PTX stabilized microtubules to induce apoptosis, while MSL counteracted COX-2/P-gp-mediated drug resistance and alleviated PTX-associated intestinal inflammation. In the AOM/DSS-induced orthotopic CRC model, KGM-PTX/CSM significantly inhibited colorectal tumor growth, improved survival rates, and suppressed inflammatory cytokine expression (TNF-α, IL-1β, IL-6, and IL-10) in serum and colorectal tissues. Immunomodulatory effects included enhanced CD8 + T-cell activity, suppression of Treg-mediated immune evasion, and macrophage polarization toward the tumor-suppressive M1 phenotype. Gut microbiota analysis demonstrated restored operational taxonomic unit (OTU) counts, increased beneficial bacterial populations, elevated alpha and beta diversity, reduced pro-inflammatory bacteria, and increased short-chain fatty acid (acetate, propionate, and butyrate) concentrations, collectively improving intestinal microecology and inhibiting tumor progression. This study synergistically enhanced the anti-CRC effect through multiple mechanisms of action such as chemotherapy, reversal of chemotherapy resistance, regulation of intestinal flora, anti-inflammation, activation of immune cells, etc., which will provide a certain reference for the research of synergistic drug therapy for CRC.
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PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2025
·
IF 4
Minna Qiu,Zhiyu Hao,Yuhao Liu,Yuhang Liu,Minghang Chang,Xu Lin,Xiumei Liu,Na Dong,Wei Sun,Xiaohua Teng
Chlorpyrifos (CPF), a toxic organophosphorus insecticide, is widely used in agriculture to protect crops (eg., maize) from pests. The use of CPF in crops can result in accumulation in crop seeds, such as corn seeds, which is a primary feed ingredient in pigs. Pigs in China, which is an important source of animal-derived protein in the Chinese diet, account for over 50 % of the raised pig population in the whole world. Therefore, CPF may pose a potential risk to the health of non-target organisms (pigs and humans) through the food chain. However, whether CPF can damage porcine intestine remains unknown. Selenium (Se), an essential trace element, was reported to have antioxidant and anti-toxic effects. Tight junction (TJ) is an important mechanism of intestinal injury and pyroptosis is a new hotspot in the field of toxicology. Hence, we wanted to investigate whether CPF can damage pig intestine and whether selenium nanoparticles (SeNPs) supplement can alleviate CPF-induced pig intestine damage, and to study corresponding mechanism from the three aspects of OS, pytoptosis, and TJ. We established a model of SeNPs alleviating damage caused by CPF in intestinal porcine enterocytes (IPEC-J2 cells), and found that SeNPs alleviated CPF-induced oxidative stress (OS), pyroptosis, and intestinal barrier dysfunction in IPEC-J2 cells. Interestingly, OS, pyroptosis, and intestinal barrier dysfunction had serial relations, and ROS/Nrf2/Caspase-1/Occludin and ROS/Nrf2/Caspase-1/ZO-1 pathways played a role. Notably, ROS and Caspase-1 played an initial and important role, respectively. Our study added new information on pesticides-caused damage to non-target organisms, and provided new idea, insight, and targets to mitigatie pesticides-induced toxic effect on non-target organisms.
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Nanoscale
·
2025
·
IF 5.1
Yuan Quan,Yan Yuan,Kejin Chen,Ting Li,Jing Li,Mengxing Zhang,Rongying Shi,Shanshan He,Lin Li,Xun Sun,Tao Gong,Ling Zhang,Zhirong Zhang,Qing Lin
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high recurrence rates, limited therapeutic options, and a strong propensity for spontaneous lung metastasis. Increasing evidence indicates that neutrophil extracellular traps (NETs) significantly promote TNBC progression, immune evasion, and metastatic dissemination, highlighting NETs inhibition as a promising therapeutic strategy. Herein, we developed a dual pH/ROS-responsive nanoplatform (pH/ROS@(PTX/SIV)) constructed from acetylated dextran (Ace-DEX) and phenylboronic acid-modified dextran (PBAP-DEX), and further functionalized with the fibronectin-targeting peptide CREKA to achieve tumor-specific accumulation. The nanoplatform enables controlled, microenvironment-responsive release of paclitaxel (PTX) and the neutrophil elastase inhibitor sivelestat (SIV) in acidic and oxidative tumor tissues. The optimized nanoparticles exhibited uniform size, high encapsulation efficiencies, and robust dual-responsive drug release. In vitro, CREKA modification markedly enhanced cellular uptake and tumor-targeting efficiency, while the dualloaded system showed superior cytotoxicity against TNBC cells. In orthotopic TNBC mouse models, pH/ROS@(PTX/SIV) significantly suppressed primary tumor growth, prolonged survival, and critically inhibited spontaneous lung metastasis.Mechanistically, the formulation effectively blocked NETs formation both in isolated primary neutrophils and in tumor tissues, thereby disrupting NETs-mediated prometastatic signaling. Furthermore, the nanoplatform displayed favorable systemic safety with negligible organ toxicity. This dual-responsive, NET-modulating nanoplatform provides a potent and safe therapeutic strategy for combating TNBC and preventing its metastasis, offering strong potential for clinical translation.
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Acta Biomaterialia
·
2026
·
IF 10.4
Huiyuan Zheng,Luxin Feng,Huan Xin,Futai Du,Yangqing Wang,Weijiang Wang,Qingming Ma,Junjie Guo,Wentao Sun
Myocardial infarction (MI) often leads to adverse ventricular remodeling, a major precursor to heart failure, while current clinical approaches remain limited in effectively promoting myocardial regeneration and suppressing fibrosis. To address these challenges, we developed an injectable, smart-responsive hydrogel integrated with catalytic nanozyme and conductive components for synergistic MI repair. The hydrogel is constructed using phenylboronic acid-modified oxidized hyaluronic acid (OHA-PBA) and dopamine-grafted gelatin (GelDA) as the backbone, cross-linked via dynamic Schiff base and boronate ester bonds, conferring rapid self-healing and specific MI microenvironment-responsive properties. This biomimetic network not only replicates the structure and function of the native extracellular matrix but also responds specifically to the acidic and highly reactive oxygen species (ROS) microenvironment within the infarcted zone, enabling on-demand drug release. Incorporated into the hydrogel are black phosphorus nanosheets (BP Ns) to restore electrical conductivity, and puerarin-loaded honeycomb-like manganese dioxide nanozymes (PHMP NPs) that act as both ROS scavengers and in situ oxygen generators. Together, these components work synergistically to promote angiogenesis, alleviate local hypoxia, and reestablish blood and oxygen supply to the ischemic tissue. This integrated platform thus concurrently delivers mechanical support, restores electrical signaling, alleviates hypoxia, and combines antioxidant, anti-inflammatory, pro-angiogenic, and anti-fibrotic capabilities, offering a comprehensive multi-target therapeutic strategy for MI. Both in vitro and in vivo evaluations demonstrate that the developed hydrogel can effectively inhibit pathological ventricular remodeling, enhance vascularization, and modulate inflammatory responses, with histopathological and transcriptomic analyses further confirming these therapeutic effects, thereby significantly promoting the recovery of cardiac functions and offering a promising and advanced therapeutic strategy for MI treatment. Statement of significance This work presents an injectable hydrogel platform that uniquely integrates electrical conductivity, catalytic oxygen generation, and smart microenvironment responsiveness for myocardial infarction (MI) therapy. Its significance lies in overcoming the limitation of current single-target approaches by enabling a synergistic multi-functional therapy. The system simultaneously restores electrical conduction, scavenges reactive oxygen species, alleviates hypoxia, and inhibits fibrosis within the infarcted heart. This integrated biomaterial strategy establishes a new paradigm for addressing the complex pathophysiology of MI, offering broad interest to researchers in biomaterials science, cardiac tissue engineering, and regenerative medicine. Download: Download high-res image (327KB) Download: Download full-size image
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2022
·
IF 5.756
Tao Wei,Zhiwei Zheng,Xiaoyan Wei,Yugang Liu,Wentao Li,Bingqing Fang,Di Yun,Zhaojun Dong,Baozhu Yi,Wulan Li,Xiaoping Wu,Dezhi Chen,Liping Chen,Jianzhang Wu
Curcumin is a natural medicine with a wide range of anti-tumour activities. However, due to β-diketone moiety, curcumin exhibits poor stability and pharmacokinetics which significantly limits its clinical applications. In this article, two types of dicarbonyl curcumin analogues with improved stability were designed through the calculation of molecular stability by density functional theory. Twenty compounds were synthesised, and their anti-tumour activity was screened. A plurality of analogues had significantly stronger activity than curcumin. In particular, compound B2 ((2E,2′E)-3,3′-(1,4-phenylene)bis(1-(2-chlorophenyl)prop-2-en-1-one)) exhibited excellent anti-lung cancer activity in vivo and in vitro. In addition, B2 could upregulate the level of reactive oxygen species in lung cancer cells, which in turn activated the endoplasmic reticulum stress and led to cell apoptosis and pyroptosis. Taken together, curcumin analogue B2 is expected to be a novel candidate for lung cancer treatment with improved chemical and biological characteristics.
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Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 35
·7931-7940
·
IF 5.344
Man Zhang,Xuequan Zhang,Shengsheng Cai,Heng Mei,Yanmei He,Dennis Huang,Wenqiang Shi,Sai Li,Jun Cao,Bin He
Molecular targeted-photodynamic combinational therapy is a promising strategy to enhance antitumor effects; meanwhile, current nanocarriers face challenges of limited selective delivery and release of therapeutic agents to specific tumor sites, which significantly compromises their therapeutic efficacy. Herein, we report active-targeting, enzyme- and ROS-dual responsive nanoparticles (HPGBCA) consisting of CD44-targeting hyaluronic acid (HA) shells and afatinib (AFT)-loaded, ROS-sensitive poly(L-lysine)-conjugated chlorin e6 (Ce6) derivative nanoparticle cores (PGBCA). HPGBCA can actively carry AFT and Ce6 specifically to tumor cells due to the negatively charged HA and CD44-mediated active targeting. Subsequently, hyaluronidase in the endosome will further spur the degradation of the HA shell to prompt exposure of the positively charged PGBCA core for rapid endosomal escape and intracellular delivery of AFT and Ce6. Furthermore, the generation of ROS produced by Ce6 under NIR irradiation can trigger the rapid oxidation of the thioether linker to facilitate the release of AFT into the cytoplasm. In vitro and in vivo studies demonstrated that the released AFT and excessive ROS at the local site can synergistically induce cell apoptosis to enhance the therapeutic efficacy without side effects. Our developed intelligent nanoparticle provides new avenues to achieve on-demand, specific intracellular drug release for improved molecular targeted-photodynamic combination therapeutic efficacy.
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