CHEMICO-BIOLOGICAL INTERACTIONS
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2026
·
IF 5.2
Manxin Chen,Haiting Sun,Shunda Zhu,Hang Yu,Yungang Liu
Phenytoin is a long standing antiepileptic drug with confirmed teratogenicity and possible carcinogenicity. Phenytoin formed electrophilic metabolite and induced oxidative DNA damage in vitro , yet it was negative in genotoxicity assays in rodents following 1∼3 d exposure. We hypothesized that extended exposure durations from regular regimens may enhance its metabolic activation and genotoxicity. In this study, male C57BL/6J mice were administered with phenytoin by gastric gavage at 5∼20 mg/kg (b.w.)/d for 7 d (5 mice in each group), then a comet assay with isolated hepatocytes, a Western blot assay of hepatic γ-H2AX (indicating double-strand DNA breaks), and a micronucleus test in the bone marrow polychromatic erythrocytes were performed. Positive results were observed in the above genotoxicity assays with phenytoin at 10 and/or 20 mg/kg/d doses, evidencing its DNA-breaking and chromosome-damaging effect. The protein levels of hepatic Cyp2c38, Cyp2c39, Cyp3a11, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) (both receptors transcriptionally regulating Cyp2c enzymes) were all increased in the 10 and/or 20 mg/kg/d phenytoin groups. Additionally, co-exposure of 1-aminobenzotriazole (100 mg/kg/d, a wide-spectrum Cyp inhibitor) blocked the genotoxic effects and phenytoin-induced Cyp2c38, 2c39 and CAR protein expression. In a mouse hepatocarcinoma (Hepa1-6) cell line, phenytoin alone induced micronucleus weakly, however, dexamethasone (DEX, 0.1 μM, a Cyp2c inducer) obviously potentiated the effect, which could be further blocked by sulfaphenazole (50 μM, a Cyp2c inhibitor). This study suggests that following 7-d oral administration phenytoin could be genotoxic in mice (potency being close to N -nitrosodiethylamine), which requires metabolic activation, possibly by Cyp2c enzymes.
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高影响因子
Toxics
·
2026
·Vol. 14
·期 8
·691
·
IF 4.9
Zhao Zhou,Hongbin Gao,Shunda Zhu,Lvlue Cai,Yijing Chen,Keqi Hu,Yungang Liu
As a commonly present organophosphorus flame retardant and persistent organic pollutant, 2-ethylhexyl diphenyl phosphate (EHDPP) has been observed to be genotoxic in cultured human hepatoma (HepG2) cells which depends on CYP activities. Yet, its impacts on hepatic Cyp expression, hepatotoxicity and genotoxicity in intact mammalians remain unidentified. In this study, adult male C57BL/6J mice received EHDPP by gastric gavage at doses of 50, 100, and 150 mg/kg (b.w.)/d for 7 d, then the hepatic expression of several Cyp proteins, aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) was analyzed by Western blotting; hepatoxicity was determined by serum ALT/AST activities and hepatic histological examination, while genotoxicity by comet assay, phosphorylated histone (γ-H2AX) protein, micronucleus test, and Pig-a assay. A micronucleus test in mouse hepatoma (Hepa1-6) cells in vitro was employed to observe the modulating effect of PCB 126 (100 nM)/BAY-218 (700 nM) (Ahr-Cyp1a1 activator/inhibitor). The results indicated that EHDPP induced hepatic Cyp1a1, 2e1, AhR, Cyp1a2, Cyp3a4 and PXR proteins and histologic liver damage at 50 mg/kg/d and/or higher doses, while at the highest dose (150 mg/kg/d) with hepatic DNA damage and micronucleus formation in bone marrow polychromatic erythrocytes. The result of Pig-a assay (at 14 and 28 d) was negative. In Hepa1-6 cells EHDPP induced micronucleus marginally; however, this effect was enhanced by PCB 126, while abolished by BAY-218. This study suggests that EHDPP may enhance protein expression of hepatic Cyp1a1, Cyp2e1, AhR and PXR and induce liver damage and DNA/chromosome damage in mice; Cyp1a1 might be a major activating enzyme.
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CELL RESEARCH
·
2023
·
IF 44.1
Ai Yuan-li,Wang Wei-jia,Liu Fan-jian,Fang Wei,Chen Hang-zi,Wu Liu-zheng,Hong Xuehui,Zhu Yuekun,Zhang Ci-xiong,Liu Long-yu,Hong Wen-bin,Zhou Bo,Chen Qi-tao,Wu Qiao
Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N -acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDME T6E or GSDME T6A knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.
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高影响因子
FOOD CHEMISTRY
·
2022
·
IF 9.231
Zhiqin Ding,Mengdie Cai,Weimin Gan,Ping Yuan,Lijun Wei,Xianglei Cheng
In this paper, a novel, selective and sensitive high performance liquid chromatography-UV photolysis-fluorescence detection (HPLC-UV-FLD) method for nitrosamines (NAs) is proposed based on terbium-doped carbon dots (Tb-CDs). Experimental studies have shown that nitrosamines can be degraded by UV photolysis with wavelength at 254 nm to produce NO 2 − , while NO 2 − can rapidly and specifically quench the fluorescence of Tb-CDs. Based on this principle, N -nitrosodimethylamine (NDMA), Nnitrosomorpholine (NMor), N -nitrosopyrrolidine (NPYR), N -nitrosodiethylamine (NDEA) and N -nitrosopiperidine (NPIP) are separated within 8 min by HPLC. These five kinds of NAs showed a good linear relationship in the range of 10–2000 μg/L, and the limit of detection was as low as 2.25 μg/L. The proposed method is successfully applied to the detection of sweet potato, lotus root, potato, water chestnut, tomato and cucumber. The sample recoveries range from 77.35 % to 119.3 %.
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Bioactive Materials
·
2022
·
IF 16.874
Yi Xiao,Haomin Yi,Jingzhi Zhu,Suhua Chen,Guofang Wang,Yilong Liao,Yuanyuan Lei,Liyin Chen,Xingcai Zhang,Fangfu Ye
Toxicity assessment is a major problem in pharmaceutical candidates and industry chemicals development. However, due to the lack of practical analytical methods for DNA adduct analysis, the safety evaluation of drug and industry chemicals was severely limited. Here, we develop a DNAzyme-based method to detect DNA adduct damage for toxicity assessment of drugs and chemicals. Among 18 structural variants of G4 DNAzyme, EA2 DNAzyme exhibits an obvious DNA damaging effect of styrene oxide (SO) due to its unstable structure. The covalent binding of SO to DNAzyme disrupts the Hoogsteen hydrogen bonding sites of G-plane guanines and affects the formation of the G4 quadruplex. DNA damage chemicals reduce the peroxidase activity of the G4 DNAzyme to monitor the DNA adduct damage by disrupting the structural integrity of the G4 DNAzyme. Our method for genotoxic assessment of pharmaceutical candidates and industrial chemicals can elucidate the complex chemical pathways leading to toxicity, predict toxic effects of chemicals, and evaluate possible risks to human health.
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高影响因子
Biomedicines
·
2023
·Vol. 11
·期 10
·2859
·
IF 4.7
Chanhao Lei,Zihan Gao,Xingzhi Lv,Yanxue Zhu,Ruifang Li,Sanqiang Li
The development of primary liver cancer (PLC) is associated with chronic liver inflammation and the loss of associated tumor suppressor genes, which characterizes inflammation-related tumors. In this study, we aimed to explore the effect of saikosaponin-b2 (SS-b2) on the development of PLC and its effect of the STK4 expression and IRAK1/NF-κB signaling axis. In vitro and in vivo experiments showed that SS-b2 exerted potent anti-inflammatory and antitumor effects. A PLC model was induced in vivo by treating male BALB/c mice with diethylnitrosamine, while an inflammatory model was induced in vitro by exposing RAW 264.7 macrophages to lipopolysaccharides (LPS). After treating cancer mice with SS-b2, the serum levels of alpha-fetoprotein, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase significantly reduced. Ki67 expression also decreased. The carcinomatous lesions of the liver were attenuated. Similar results were observed in liver tissue and RAW 264.7 macrophages, where SS-b2 significantly elevated serine/threonine protein kinase 4 (STK4) expression and decreased the expression of interleukin-1 receptor–associated kinase 1 (IRAK1), nuclear factor-kappaB (NF-κB), and downstream inflammatory cytokines, thus exerting anti-cancer and anti-inflammatory effects. Moreover, we employed siRNA to silence the STK4 expression in HepG2 to investigate the anti-tumor effect of SS-b2 in vitro. The STK4 knockdown would upregulate IRAK1 and thus the activation of NF-κB activity revealed by the increase in the levels of proinflammatory cytokines, consequently impairing SS-b2-induced inhibition of liver cancer development. Consequently, SS-b2 effectively inhibited PLC by upregulating STK4 to suppress the IRAK1/NF-κB signaling axis and is a promising agent for treating this disease.Keywords:primary liver cancer;saikosaponin-b2;serine/threonine protein kinase 4;interleukininterleukin-1 receptor-associated kinase 1;nuclear factor-kappa B
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TETRAHEDRON
·
2020
·
IF 2.233
Jian Chen,Kai Chen,Baichuan Han,Yunting Xue,Wanjuan Chen,Zhenzhong Gao,Xianfeng Hou
A single-fluorophore-based ratiometric fluorescent probe based on anthracene carboximide was developed for detection of formaldehyde. In the presence of formaldehyde, the fluorescence emission would change from red to yellow-green, and the probe showed excellent sensitivity, selectivity and anti-interference. Furthermore, the response mechanism was illustrated to be that change in fluorescent signal is resulted from variation of substituent group on the 6th position of anthracene ring. A test paper was developed by loading probe onto filter paper strip. With this test paper, the detection of gaseous formaldehyde could be carried out conveniently, visually and quickly. 2009 Elsevier Ltd. All rights reserved.
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EXPERIMENTAL CELL RESEARCH
·
2024
·
IF 3.3
Jun Yan,Yunfei Zhou,Jianwen Xu,Yihong Dong,Xun Yang,Xinxin Yang,Aodi Wu,Shuyuan Chang,Yumeng Wang,Qingxin Zhang,Tomii Ayaka,Lei Yu,Liuyang Zhao,Hongxue Meng,Dabin Liu
Lactylation is an emerging pathogenesis of hepatocellular carcinoma (HCC). However, the underlying mechanisms and biological significance remain poorly understood. The Carbonic anhydrase III (CA3) gene, previously defined as a binding protein of SQLE and involved in the NAFLD disease, has now been identified as a novel tumor suppressor in HCC. mRNA expression of CA3 is associated with a favorable prognosis and negatively correlated with serum lactate levels, whereas CA3 protein expression does not correlate with patient prognosis or serum lactate levels, suggested there has lactate-related post-translational modification of CA3 in HCC. Overexpression of CA3 induces cell apoptosis, thereby reducing intracellular reactive oxygen stress (ROS) through the inhibition of DUOX2 expression. The decreased lactylation level of CA3 protein at the K36 residues, induced by SQLE, results in the loss of the anti-cancer effect of CA3. Together, this study has demonstrated that CA3 is a novel tumor suppressor in HCC, and delactylation of CA3 represents a newly identified mechanism by which HCC cells evade growth suppressors.
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高影响因子
WATER AIR AND SOIL POLLUTION
·
2018
·Vol. 229
·期 3
·1-11
·
IF 1.769
Huang Danping,Li Hanmin,He Qidi,Yuan Weiqu,Chen Zuanguang,Yang Hongzhi
Diethylnitrosamine (DEN) is present in food, water, and daily supplies and is regarded as a toxicant of carcinogenicity. The developmental toxicity of DEN has been rarely reported as yet. In this study, zebrafish were exposed to different concentrations of DEN at 6 h post-fertilization (hpf) to access embryonic toxicity of the compound. The results show that DEN resulted in negative effects of hatching rate, heartbeat, body length, and spontaneous movement. Deformities, including notochord malformation, pericardium edema, embryonic membrane turbidity, tail hypoplasia, yolk sac deformity, and growth retardation, happened during exposure period. Moreover, production of reactive oxygen species (ROS) significantly increased after DEN treatment. Then, alterations of the expression level of oxidative stress-related genes were observed in our results. To our knowledge, this is the first study concerning the effect of DEN on zebrafish. And from the information of our research, we speculated that development toxicity of DEN should be related to the excessive oxidative stress.
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Journal of Pharmaceutical Analysis
·
2024
·
IF 6.1
Xin Yang,Guang-Yuan Ma,Xiao-Qiang Li,Na Tang,Yang Sun,Xiao-Wei Hao,Ke-Han Wu,Yu-Bo Wang,Wen Tian,Xin Fan,Zezhi Li,Caixia Feng,Xu Chao,Yu-Fan Wang,Yao Liu,Di Li,Wei Cao
Hepatocellular carcinoma (HCC) expresses abundant glycolytic enzymes and displays comprehensive glucose metabolism reprogramming. Aldolase A (ALDOA) plays a prominent role in glycolysis; however, little is known about its role in HCC development. In the present study, we aim to explore how ALDOA is involved in HCC proliferation. HCC proliferation was markedly suppressed both in vitro and in vivo following ALDOA knockout, which is consistent with ALDOA overexpression encouraging HCC proliferation. Mechanistically, ALDOA knockout partially limits the glycolytic flux in HCC cells. Meanwhile, ALDOA translocated to nuclei and directly interacted with c-Jun to facilitate its Thr93 phosphorylation by P21-activated protein kinase; ALDOA knockout markedly diminished c-Jun Thr93 phosphorylation and then dampened c-Jun transcription function. A crucial site Y364 mutation in ALDOA disrupted its interaction with c-Jun, and Y364S ALDOA expression failed to rescue cell proliferation in ALDOA deletion cells. In HCC patients, the expression level of ALDOA was correlated with the phosphorylation level of c-Jun (Thr93) and poor prognosis. Remarkably, hepatic ALDOA was significantly upregulated in the promotion and progression stages of diethylnitrosamine-induced HCC models, and the knockdown of ALDOA strikingly decreased HCC development in vivo . Our study demonstrated that ALDOA is a vital driver for HCC development by activating c-Jun-mediated oncogene transcription, opening additional avenues for anti-cancer therapies.
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BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Lingli Jiang,Rui Liang,Qing Luo,Zhe Chen,Guanbin Song
Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays critical oncogenic roles in multiple cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in patients with HCC. Genetic depletion of Fto dramatically attenuated HCC progression in mice. Pharmacological inhibition of FTO by FB23/FB23-2 markedly suppressed the proliferation and migration of HCC cell lines in vitro and inhibited HCC tumorigenicity in xeno-transplanted mice. Mechanistically, FB23-2 suppressed the expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) and human tubulin beta class Iva (TUBB4A) by increasing the m6A level in these mRNA transcripts. The decrease in ERBB3 expression resulted in the inhibition of Akt-mTOR signaling, which subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 disturbed the stability of the tubulin cytoskeleton, whereas overexpression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrates that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells and highlights the potential of FTO inhibitors for targeting HCC.
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iScience
·
2025
·
IF 4.1
Shuyuan Chang,Ayaka Tomii,Yunfei Zhou,Xun Yang,Yihong Dong,Jun Yan,Aodi Wu,Yumeng Wang,Qingxin Zhang,Hongxue Meng,Lei Yu,Wei Sun,Dabin Liu
Succinate is a crucial metabolite in the TCA cycle and contributes to cancer development. However, the role of exogenous succinate in hepatocellular carcinoma (HCC) is unclear. Here, we report that the concentration of succinate in HCC tissues is lower compared to adjacent normal tissues, as determined by spatial metabolomics and quantitative metabolomics analysis. Succinate supplementation exhibits an anti-tumorigenic effect, inhibiting cell proliferation and colony formation in liver cancer cells but not in non-tumor LO2 cells. Additionally, succinate supplementation significantly reduces tumor formation in xenograft nude mice models and carcinogen-induced WT mice models. The anti-tumorigenic function of succinate is mechanistically mediated by FN1-activated SQLE-related cholesterol biosynthesis. Our study demonstrates that exogenous succinate acts as a cholesterol biosynthesis inhibitor to suppress HCC both in vitro and in vivo , highlighting its potential therapeutic applications.
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