ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2026
·
IF 6.6
Qingyang Li,Wei Zhu,Xiao Han,Peiyu Yang,Changhao Liu,Rubing Zou,Shuying Li,Yihua Liu,Yirong Guo
CPF and TCP showed distinct triglyceride-rich lipidomic profiles. • CPF broadly reprogrammed lipid synthesis and xenobiotic metabolism. • TCP-associated lipid disruption involved mitochondrial energy dysfunction. • Co-exposure increased triglyceride accumulation and expanded gene–lipid networks. Metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasingly linked to environmental chemical exposure, yet the metabolic consequences of pesticide parent–metabolite co-exposure remain poorly understood. HepG2 cells were exposed for 48 h to chlorpyrifos (CPF, 10 mg/L), its major metabolite 3,5,6-trichloro-2-pyridinol (TCP, 1.25 mg/L), or their combination (CTCP). Network toxicology was applied for hypothesis generation, followed by integrated lipidomics and transcriptomics analyses. Under the selected exposure conditions, TCP induced greater lipid-droplet accumulation than CPF despite the lower nominal concentration. Lipidomic profiling revealed that both compounds promoted triglyceride accumulation accompanied by extensive remodeling of cholesterol esters, free fatty acids, phospholipids, and sphingolipids. Transcriptomic analysis indicated that CPF elicited a broader response characterized by CYP-mediated xenobiotic metabolism and lipid-handling pathways, whereas TCP exhibited a more restricted signature associated with energy homeostasis and stress-related pathways. Functional assays further supported these distinct responses, showing that TCP exposure reduced ATP levels and increased reactive oxygen species generation, consistent with disrupted cellular energetic and redox homeostasis, while CPF increased cellular CYP1A2 protein levels. Compared with individual exposures, CTCP was associated with greater lipid accumulation and broader transcriptomic and lipidomic alterations involving membrane remodeling, altered cellular energy homeostasis, and changes in inflammation-associated lipid pathways. CPF and TCP produced distinct but overlapping MASLD-relevant lipid metabolic alterations, and their co-exposure produced greater metabolic alterations than either individual exposure under the tested conditions. These findings highlight the importance of considering pesticide metabolites and parent–metabolite co-exposure in environmental health risk assessment.
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DOI
高影响因子
Nanomaterials
·
2025
·Vol. 15
·期 8
·615
·
IF 4.3
Ren Li,Yi Zhu
Sulforaphane (SFN) is a natural isothiocyanate compound with multiple bioactive effects, abundantly found in cruciferous vegetables. SFN and cadmium (Cd) were limited in their application as chemotherapeutic agents due to insufficient cellular uptake, low bioavailability, and high systemic toxicity, respectively. In this study, mPEG-PLGA nanoparticles were used as a carrier to load Cd-γ-PGA conjugates and SFN, enabling favorable drug release under acidic microenvironments with excellent pH responsiveness. The NP-Cd-SFN nanoparticles exhibited a particle size of 102.1 nm, a zeta potential of -14.48 mV, and a PDI value of 0.257. These characteristics contribute to the nanoparticles’ prolonged circulation in the bloodstream and their ability to passively target tumors. Compared to the single-dose groups and the combined Cd + SFN group, the NP-Cd-SFN group significantly reduced the viability of HepG2 cells and increased their apoptosis rate by inducing mitochondrial oxidative stress and promoting cell apoptosis. Overall, the addition of SFN and the encapsulation of mPEG-PLGA enhanced the therapeutic effects of Cd on HepG2 cells.
研究领域:
药剂学
·
肿瘤学
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DOI
PubMed
高影响因子
MICROCHEMICAL JOURNAL
·
2025
·
IF 5.1
Huifang Zhao,Xiunan Xu,Mi Shi,Yi Chen,Bowei Guan,Fujuan Peng,Jinze Li,Yuanyuan Zhao,Lu Zhang,Ruiping Zhang
Spatial lipidomics analysis of three-dimensional (3D) tumor cell spheroids enables in-situ investigation of metabolic reprogramming across distinct regions cellular regions within a single spheroid. However, it is still a challenge to study the effect of 5-fluorouracil (5-FU) with 3D HepG2 spheroid on the alteration of abundance and spatial distribution of endogenous lipid species. Herein, we systematically optimized the matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) methodologies for extending spatial lipidomics to in-situ screening and visualizing lipid changes in 3D HepG2 spheroids treated with 5-FU at the microregional level. The embedding protocols in carboxymethyl cellulose (CMC), gelatin, and optimal cutting temperature (OCT) compound of 3D HepG2 spheroid were evaluated for MALDI MSI analysis with 10 μm spatial resolution, respectively. Subsequently, CMC embedding of 3D HepG2 spheroid completely preserved the 3D spatial structure and enabled the division into the core necrotic area, intermediate quiescent area, and outer proliferative area from the spatial lipidic ion spectra. Furthermore, we spatially screened and identified 35, 40, and 30 distinct lipid molecules associated with 5-FU treatment in the 3D HepG2 spheroid of necrotic, quiescent, and proliferative areas, respectively. The main dysregulated metabolic pathway was the biosynthesis of glycerophospholipid metabolism, providing the reliable evidence for the mechanism of 5-FU anticancer effect on hepatocellular carcinoma (HCC). In addition, the spatial lipidomic results demonstrated that PA, PC, PG, PI, and SM contents in 5-FU treated tumor spheroids were significantly changed and limited the formation of the central necrotic area. This innovative combination of MALDI MSI with 3D HepG2 spheroids can be conducive to our better understanding of the biological processes between 5-FU triggered lipid metabolism and HCC heterogeneous structure.
研究领域:
肿瘤学
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分子生物学
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药理学
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代谢组学
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转化医学
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肝病学
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DOI
高影响因子
RSC Advances
·
2018
·Vol. 8
·期 71
·40984-40988
·
IF 2.936
Xiaonan Gao,Wenfei Guo,Lihong Ge,Fanpeng Kong,Kehua Xu,Bo Tang
Sodium selenite (Na2SeO3), as an anti-tumor drug for inducing tumor cells' apoptosis, has been widely studied under normoxic conditions and has been shown to exhibit oxidative stress process-induced apoptosis. However, since the real tumor environment is hypoxic, the actual mechanism is still unclear. Hence, considering the main metabolite of Na2SeO3 in the metabolic process to be hydrogen selenide (H2Se) and also that it can be converted to superoxide anion (O2˙−) instantaneously in the presence of oxygen, a dual-ratiometric fluorescence imaging system for simultaneous monitoring of the changes of H2Se and O2˙− induced by Na2SeO3-guided tumor cell apoptosis under hypoxic conditions was constructed. Two molecular probes NIR-H2Se and dihydroethidium were used to detect H2Se and O2˙−, respectively, whereas Rhodamine 110 was used as the reference fluorophore. Notably, H2Se levels significantly increased under hypoxic conditions, but there was no change in the level of O2˙−, which is inconsistent with the results of the previous researches. Therefore, we hypothesize that the mechanism of Na2SeO3-induced apoptosis for tumor cells is caused by reductive stress; also, this method can be applied for the future study of other anti-cancer selenium compounds.
研究领域:
生物化学
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医学影像学
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肿瘤学
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DOI
高影响因子
JOURNAL OF FOOD BIOCHEMISTRY
·
2021
·Vol. 45
·期 11
·e13976
·
IF 2.72
Longkai Shi,Emad Karrar,Xingguo Wang
Non-alcoholic fatty liver disease (NAFLD) is a chronic hepatopathy caused by disordered lipid metabolism in the liver. Sesamol, a phenolic compound derived from sesame oil, has been shown to inhibit obesity, hyperlipidemia, and atherosclerosis in previous investigations. However, the preventive effect of sesamol against hepatic steatosis and oxidative stress in NAFLD has not been well-studied. In this work, sesamol was observed to alleviate lipid accumulation and oxidative stress in high oleic acid (300 μM)/cholesterol (25 μM) induced HepG2 cells, thus indicating that sesamol was involved in regulating hepatic lipid metabolism and oxidative injury. Mechanism studies found that the activated peroxisome proliferator-activated receptors (PPAR) signaling pathway by sesamol intervention up-regulated gene and protein expressions related to fatty acid oxidation and cholesterol efflux and catabolism, thus accelerating lipid consumption and reducing intracellular lipid accumulation in the process of NAFLD. These data suggested that sesamol can effectively ameliorate hepatic steatosis and sesamol riched sesamol oil may be a potential agent for finding therapeutic strategies to treat the NAFLD. Practical applications Sesamol and sesamol-rich sesame oil have received much attention due to their performance on hepatic lipid regulation. The results of this study indicate that sesamol treatment could ameliorate hepatic steatosis by inhibiting lipid accumulation and oxidative stress, thus demonstrating that sesamol and sesame oil can be used for functional foods and nutraceutical applications in the future. In addition, the present work provides knowledge of the effects of sesamol on NAFLD and involved mechanisms, and further supplies nutritional guidelines for sesame oil consumption.
研究领域:
营养学
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分子生物学
·
医学
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产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2019
·
IF 5.108
Quan Chi,Wenxiang Zhang,Lang Wang,Juan Huang,Ming Yuan,Huaming Xiao,Xian Wang
Brominated flame retardants (BFRs) are found at quantifiable levels in both humans and wildlife and may potentially cause a health risk. For BFRs and their derivatives, limited information regarding the relationship among the structure, binding affinity to the target protein and toxicity is currently available. In the present work, representative BFRs with different hydroxyl- or bromo-substituents, namely 2, 2′, 4, 4′-tetrabromodiphenyl ether (BDE-47), 3-hydroxy-2, 2′, 4, 4′-tetrabromodiphenyl ether (3-OH-BDE-47) and tetrabromobisphenol A (TBBPA), were selected to investigate the interactions with transthyretin (TTR) by electrospray ionization mass spectrometry (ESI-MS) and cytotoxicity on HepG2 cells. It was noted that BDE-47 had a weak binding affinity to TTR, while 3-OH-BDE-47 and TBBPA had a stronger binding affinity than BDE-47 and thyroxine (T4). Hence, 3-OH-BDE-47 and TBBPA could affect the binding of TTR with its native ligand T 4 by competitive binding to TTR, even at equal concentrations, which might be associated with BFR toxicity of endocrine disruption. Negative cooperativity was found for 3-OH-BDE-47 and TBBPA binding to TTR, similar to T 4 with a well-established negatively cooperative binding mechanism. The tendency of toxic effects on HepG2 cells for these three BFRs was, 3-OH-BDE-47 > TBBPA > BDE-47, and this order was in good agreement with the binding ability explored by ESI-MS experiments and molecular docking simulation. The observations obtained by this study demonstrate that the binding properties of these BFRs to TTR and their cytotoxicity are correlated with structure differentials and functional substituents.
研究领域:
环境科学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 2
·1081
·
IF 4.9
Yi Liu,Yang Ge,Yanfan Wu,Yongtong Feng,Han Liu,Wei Cao,Jinsong Xie,Jingzhong Zhang
Three-dimensional (3D) hepatocyte models have become a research hotspot for evaluating drug metabolism and hepatotoxicity. Compared to two-dimensional (2D) cultures, 3D cultures are better at mimicking the morphology and microenvironment of hepatocytes in vivo. However, commonly used 3D culture techniques are not suitable for high-throughput drug screening (HTS) due to their high cost, complex handling, and inability to simulate cell–extracellular matrix (ECM) interactions. This article describes a method for rapid and reproducible 3D cell cultures with ECM–cell interactions based on 3D culture instrumentation to provide more efficient HTS. We developed a microsphere preparation based on a high-voltage electrostatic (HVE) field and used sodium alginate- and collagen-based hydrogels as scaffolds for 3D cultures of HepG2 cells. The microsphere-generating device enables the rapid and reproducible preparation of bioactive hydrogel microspheres. This 3D culture system exhibited better cell viability, heterogeneity, and drug-metabolizing activity than 2D and other 3D culture models, and the long-term culture characteristics of this system make it suitable for predicting long-term liver toxicity. This system improves the overall applicability of HepG2 spheroids in safety assessment studies, and this simple and controllable high-throughput-compatible method shows potential for use in drug toxicity screening assays and mechanistic studies.Keywords:hepatocyte;3D cultures;hydrogel;microspheres;high-voltage electrostatic field;RNA-seq
研究领域:
细胞生物学
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药理学
·
毒理学
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DOI
PubMed
高影响因子
Frontiers in Nutrition
·
2026
·
IF 5.5
Hong Wang,Bingqi Huang,Wenhong Zhao,Gongliang Liu,Weidong Bai
Introduction Chinese olive ( Canarium album L.) is a rich source of phenolic compounds and has been suggested to exhibit distinct lipid-lowering bioactivities from those reported for Mediterranean olive polyphenols. Methods This study investigated the effects of polyphenol-rich Chinese olive extracts on sodium oleate-induced lipid accumulation in HepG2 cells. Results Treatment with extracts was associated with a significant reduction in intracellular total lipid and triglyceride levels in a concentration-dependent manner. RT-qPCR results revealed that extract treatment was accompanied by the downregulation of lipogenesis-related genes (SREBP-1c, ACC1, FASN, and DGAT2) and the upregulation of β -oxidation-associated genes (PGC-1α, PPARα, CPT-1A, and ACOX1). Western blot analysis showed that extract treatment was associated with AMPK phosphorylation, occurring concurrently with the observed lipid-associated changes. Furthermore, treatment with extracts was accompanied by decreased expression of miR-122 and miR-21, which correlated with the expression of their respective lipid-metabolism target genes. UPLC–MS/MS analysis identified 39 phenolic compounds in the extract, including methyl brevifolincarboxylate and ellagic acid derivatives, indicating a complex phenolic composition. Discussion These results demonstrate that attenuation of lipid accumulation by polyphenol-rich Chinese olive extracts in HepG2 cells is accompanied by AMPK phosphorylation and miRNA modulation. This finding supports the potential of Chinese olive extracts as a natural hepatoprotective ingredient for the development of functional foods and nutraceuticals.
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DOI
PubMed
高影响因子
JOURNAL OF ENVIRONMENTAL MANAGEMENT
·
2025
·
IF 8.4
Xiaotian Huang,Zuhong Lin,Denglong Lu,Haipu Li
Tetrabromobisphenol A (TBBPA), a brominated flame retardant extensively used in consumer electronics, has been classified as a persistent environmental contaminant. While TBBPA-induced mitochondrial dysfunction is implicated in apoptosis, the precise oxidative stress-mediated mechanisms remain incompletely characterized. In this study, using human liver cancer cells (HepG 2 ) as an in vitro model, we systematically investigated TBBPA's mitochondrial toxicity and associated cell death pathways. In vitro assays demonstrated that 10 μM TBBPA induced approximately 50 % cell death and reduced cell viability. This treatment also markedly elevated intracellular reactive oxygen species (ROS) levels. A comprehensive analysis of mitochondrial function, including assessments of mitochondrial membrane potential (MMP), oxygen consumption rate (OCR), ATP production, respiratory chain complex activities, and mitochondrial autophagy markers (LC3B, PINK1, Parkin), revealed that TBBPA entry into cells resulted in mitochondrial dysfunction. Furthermore, Ferroptosis biomarkers quantification further revealed TBBPA-driven Fe 2+ and malondialdehyde (MDA) accumulation, coupled with upregulated expression of ferroptosis-related proteins (GPX4, SLC7A11, COX-2, Beclin-1). These findings provide novel insights into the molecular pathways underlying TBBPA-induced cytotoxicity.
研究领域:
毒理学
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细胞生物学
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环境科学
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产品关联
DOI
PubMed
高影响因子
MACROMOLECULAR BIOSCIENCE
·
2016
·Vol. 16
·期 5
·774-783
·
IF 3.68
Tieshi Wang,Xinde Tang,Jingtian Han,Yuanyuan Ding,Wenjuan Guo,Meishan Pei
Biodegradable self-assembled polymeric nanoparticles (NPs) composed of poly(6- O -methacryloyl-D-galactopyranose)- b -poly(L-lactide)- b -poly(6- O -methacryloyl-D-galactopyranose) (PMAGP- b -PLA- b -PMAGP) are prepared as carriers for the hydrophobic anticancer drug paclitaxel (PTX), to achieve target delivery to hepatoma cells. PTX can be encapsulated by the NPs with various molar ratios of L-lactide (LA) and 6- O -methacryloyl-D-galactopyranose (MAGP) during the process of self-assembly, and the resulting NPs exhibit high drug loading efficacy and substantial stability in aqueous solution. The size, size distribution, and morphology of the NPs are characterized using a Zetasizer Nano ZS and transmission electron microscopy. The hemolysis assay and cell cytotoxicity assay indicate that the polymeric NPs are biocompatible and non-toxic. The cellular uptake assay demonstrates that the galactose-containing NPs can be selectively recognized and subsequently accumulate in HepG2 cells. All of these results demonstrate that galactose-containing polymeric NPs are potential carriers for hepatoma-targeted drug delivery and liver cancer therapy in clinical medicine.
研究领域:
药剂学
·
肿瘤学
·
生物材料学
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DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2018
·Vol. 16
·期 2
·925-930
·
IF 1.41
Wen‑Jie Li,You‑Wen Lian,Quan‑Sheng Guan,Ning Li,Wen‑Jun Liang,Wen‑Xin Liu,Yong‑Bin Huang,Yi Cheng,Hui Luo
Liver‑targeted drug delivery improves the efficacy of anti‑liver cancer agents and reduces systemic toxicity by limiting the bioavailability of these drugs to within tumors. Liver targeting reagents with galactose residues, which selectively combine to asialoglyco protein receptors, have previously been used to improve liposome‑encapsulated drug accumulation within liver cells. They lead to a reduction in liver cancer cell growth and have been used to cure certain hepatic diseases. In the present study, curcumol, which is the primary active component of Chinese traditional medicine Rhizoma zedoariae, was encapsulated in galactosylated‑liposomes to enhance its anti‑liver cancer efficacy. Galactosylated‑liposomes and normal liposomes were labeled with propidium iodide. Galactosylated‑liposomes with increasing concentrations of galactosylated‑stearate (Gal‑s) had a notably increased level of uptake in HepG2 cells (hepatoblastoma) compared with SGC‑7901 (gastric cancer) and A549 (non‑small cell lung cancer) cells. When the percentage of Gal‑s reached 20%, liposome uptake plateaued. In the in vitro anti‑liver cancer experiment, the anti‑liver cancer efficacy of galactosylated‑curcumol‑liposomes increased significantly more compared with normal curcumol liposomes and free curcumol as indicated by cell survival rate and lactate dehydrogenase release rate. Collectively, these results demonstrate that galactosylated‑liposomes are able to enhance the in vitro liver‑targeting effect and anti‑liver cancer efficacy of curcumol.
研究领域:
药理学
·
肿瘤学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2021
·
IF 6.953
Linan Zhou,Ziteng Song,Shaojie Zhang,Yeling Li,Jing Xu,Yuanqiang Guo
Selenium nanoparticles (SeNPs), a potential cancer therapeutic agent, have attracted widespread attention owing to their high bioavailability and remarkable anticancer activity. Nevertheless, the poor water solubility and dispersibility of SeNPs seriously limit their applications. In the present study, we synthesized stable and individual spherical selenium nanoparticles (CL90-Tw-SeNP2) with an average diameter of approximately 79 nm using a polysaccharide extracted from Citrus limon (CL90) and Tween-80 as the decorator and stabilizers. The proportion of selenium in CL90-Tw-SeNP2 was 10.6%. CL90-Tw-SeNP2 possessed high stability and good dispersion in water for more than three months. The subsequent biological assay revealed that CL90-Tw-SeNP2 showed remarkable antitumor effects against HepG2 cells, with an IC 50 value of 49.13 μg/mL, by inducing cell apoptosis. Furthermore, an in vivo zebrafish assay to explore possible applications indicated that CL90-Tw-SeNP2 could inhibit the proliferation and migration of tumors and the zebrafish angiogenesis. These results indicated that CL90-Tw-SeNP2 could be a potential agent for cancer treatment, especially against human liver hepatoma cancer.
研究领域:
纳米技术
·
药学
·
癌症研究
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）