JOURNAL OF TRACE ELEMENTS IN MEDICINE AND BIOLOGY
·
2025
·
IF 3.3
Ziyan Han,Yuzhou Zhuo,Zhihui Dai,Xinhui Zhang,Bingqian Zhu,Yuyan Liu,Zhuoyu Chai,Jiayi Wu,Lijun Chen
Background Cinnabar is a mercury-containing mineral traditionally used in Chinese medicine and can induce kidney injury via mercury toxicity. Given that cinnabar contains elements such as selenium, it is reasonable to hypothesize that its multi-element composition may regulate nephrotoxicity through intermetallic interactions. To validate this hypothesis and clarify the distinct renal toxicity between cinnabar and single mercury compounds, we compared the nephrotoxic effects of cinnabar, Zhu-Sha-An-Shen-Wan (ZSASW), mercuric sulfide (HgS), and mercuric nitrate (Hg(NO₃)₂). By co-administration with sodium selenite (Na₂SeO₃), this study related to the nephrotoxicity of cinnabar was improved from the perspective of metal-element interactions, which provided a new perspective for the safety assessment of mercury-containing medicines. Methods Mice were gavaged with 0.5 % CMC-Na solution, cinnabar (50.0 and 200 mg/kg), HgS (50.0 mg/kg), Na 2 SeO 3 (1.00 mg/kg), cinnabar (50.0 mg/kg)+Na 2 SeO 3 (1.00 mg/kg), HgS (50.0 mg/kg)+Na 2 SeO 3 (1.00 mg/kg), ZSASW (600 mg/kg), ZSASW (600 mg/kg)+Na 2 SeO 3 (1.00 mg/kg) or Hg(NO 3 ) 2 (0.900 mg/kg in Hg 2+ ) daily for 30 days. Renal histopathology was assessed by H&E staining. Related protein expression was measured by Western blotting. Renal total Hg (THg) concentration in kidney was determined by cold vapor atomic fluorescence spectroscopy. Result Western blotting revealed significantly decreased OAT1 and GPX4 levels in all experimental groups compared to the Control group ( P < 0.05). NF-κB activation occurred in the Hg(NO₃)₂, Cinnabar-H, HgS, and HgS-Na₂SeO₃ groups. Hg(NO₃)₂ administration caused a significant decline in body weight growth rate ( P < 0.001), severe renal tubular degeneration with epithelial cell swelling, and the highest renal THg concentration (773.77 % exceeding the Control group). Na₂SeO₃ alone induced inflammatory infiltration and tubular epithelial degeneration. The Cinnabar-H and HgS groups exhibited distinct renal damage (localized tubular degeneration and vascular hyaline degeneration, respectively) with elevated renal THg concentration (330.74 % and 347.95 % exceeding the Control group). The Cinnabar-L, Cinnabar-Na₂SeO₃, ZSASW, and ZSASW-Na₂SeO₃ groups maintained normal histology despite increased renal mercury content (227.46 %, 40.57 %, 67.2 %, and 556.56 % exceeding the Control group). Co-administration of Na₂SeO₃ with HgS restored OAT1 and GPX4 expression ( P < 0.001), suppressed NF-κB activation, and minimally altered renal mercury accumulation (RSD=0.45 %). Na₂SeO₃ reduced mercury levels in the cinnabar-treated mice (57.07 % reduction) but increased accumulation in ZSASW-treated mice (292.65 % increase). Conclusion This study confirms that cinnabar and ZSASW exhibit lower toxicity than mercuric sulfide or mercuric nitrate. Multi-component synergistic or antagonistic effects need to be considered when studying the mechanism of action of cinnabar-related drugs.
研究领域:
毒理学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2021
·
IF 8.071
Rili Hao,Xinyu Song,Dongxiao Sun-Waterhouse,Xintong Tan,Feng Li,Dapeng Li
Cadmium (Cd), as an environmental pollutant, can lead to nephrotoxicity. However, its nephrotoxicological mechanisms have not been fully elucidated. In this study, Cd (1.5 mg/kg body weight, gavaged for 4 weeks) was found to induce the renal damage in mice, based on indicators including Cd concentration, kidney index, serum creatinine and blood urea nitrogen levels, pro-inflammatory cytokines and their mRNA expressions, levels of Bcl-2, Bax and caspase9, and histopathological changes of the kidneys. Furthermore, Cd-caused detrimental changes through inducing inflammation and apoptosis via the miR-34a/Sirt1/p53 axis. This is the first report on the role of miR-34a/Sirt1/p53 axis in regulating Cd-caused apoptosis and nephrotoxicity in mice. The findings obtained in this study provide new insights into miRNA-based regulation of heavy metal induced-nephrotoxicity.
研究领域:
毒理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Toxics
·
2023
·Vol. 11
·期 6
·479
·
IF 4.6
Tao Wei,Na Cao,Tiantian Han,Yi Chen,Xingtao Zhou,Liyang Niu,Wenting Liu,Chang Li
3-monochloropropane-1,2-diol (3-MCPD) is a food-process toxic substance, and its main target organ is the kidney. The present study examined and characterized the nephrotoxicity and the lipidomic mechanisms in a model of kidney injury in Sprague Dawley (SD) rats treated with high (45 mg/kg) and low (30 mg/kg) doses of 3-MCPD. The results showed that the ingestion of 3-MCPD led to a dose-dependent increase in serum creatinine and urea nitrogen levels and histological renal impairment. The oxidative stress indicators (MDA, GSH, T-AOC) in the rat kidney altered in a dose-dependent manner in 3-MCPD groups. The lipidomics analysis revealed that 3-MCPD caused kidney injury by interfering with glycerophospholipid metabolism and sphingolipid metabolism. In addition, 38 lipids were screened as potential biomarkers. This study not only revealed the mechanism of 3-MCPD renal toxicity from the perspective of lipidomics but also provided a new approach to the study of 3-MCPD nephrotoxicity.Keywords:3-MCPD;nephrotoxicity;lipidomics;biomarkers;pathway
研究领域:
毒理学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2025
·
IF 8
Jing Lu,Hongdi Wei,Xinyu Yao,Yuelin Chen,Meitong Liu,Shuang Guan
Glycidol is a common food contaminant, and its main target organ is the kidney. However, the mechanism of nephrotoxicity of glycidol has not been fully elucidated. In this paper, we investigated the mechanism of glycidol toxicity in mice kidneys and NRK-52E cells. We found that glycidol exposure induced necroptosis in renal cells through the RIPK1/RIPK3/MLKL pathway. Mechanistically, it was further found that glycidol blocked renal cell autophagy and induced ectopic aggregation of p62. Accumulated p62 recruited RIPK1 and activated downstream RIPK1/RIPK3/MLKL necrosome production. At the same time, the accumulated p62 could also participate in the activation of intracellular NF-κB nuclear transcription factor by interacting with RIPK1 to form a signalling complex, which promoted the secretion of inflammatory factors TNF-α and IL-1β, and induced inflammation in the kidney. Our present study provided a new understanding of the complex mechanism of glycidol on renal injury.
研究领域:
毒理学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2024
·
IF 4.2
Hongmin Lu,Yue Zhang,Xin Zhang,Ruoqi Wang,Tiantian Guo,Qi Wang,Hongjing Zhao,Mingwei Xing
Environmental pollution caused by arsenic or its compounds is called arsenic pollution. Arsenic pollution mainly comes from people mining and smelting arsenic compounds. In addition, arsenic compounds' widespread use and production of arsenic-containing pesticides, arsenic-rich water used to irrigate farms, or high arsenic levels in foods caused by coal burning are all sources of arsenic contamination. Arsenic contamination poses a significant threat to global public health. It is reported that exposure to arsenic can induce severe renal injury. However, the underlying mechanism needs to be clarified. In this study, the arsenic exposure model in vivo and in vitro was used to explore the mechanism of arsenic-induced renal injury, especially the role of ferroptosis and its regulatory mechanism, and then to evaluate its anti-pollution effect by supplementing zinc. The results showed that arsenic significantly induced ferroptosis, characterized by up-regulating the expression of YAP and TFR in kidney and CIK cells and then increasing the levels of Fe 2+ and ROS, lipid peroxidation, and iron metabolism. Microscopic observation revealed the shrinkage of mitochondria and the increase in membrane density. In addition, molecular docking and inhibitor experiments further confirmed that arsenic is involved in the process of ferroptosis by activating YAP and TFR. These results clarify the harmful effects of arsenic on carp kidneys and its mechanism and highlight the critical interactions between the YAP-TFR pathway, ROS, and ferroptosis. Importantly, this study found that zinc can reduce ferroptosis caused by the arsenic-activated YAP-TFR pathway by inhibiting YAP activation and lipid peroxidation.
研究领域:
环境科学
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毒理学
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水生生物学
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产品关联
DOI
PubMed
高影响因子
Toxicology Research
·
2018
·Vol. 7
·期 6
·1205-1213
·
IF 1.89
Qiu Xuan,Zhou Xiaobing,Miao Yufa,Li Bo
The kidney is one of the major target organs for drug-induced toxicity. During drug development, the traditional markers of nephrotoxicity indicate only severe and late damage, which leads to high costs. The new biomarkers are needed for a more sensitive and reliable evaluation of nephrotoxicity, especially for the regulatory accepted and validated in vitro model. We developed an in vitro model based on the HK-2 cell using the biomarkers of nephrotoxicity as endpoints for the evaluation of nephrotoxicity. The predictive performance of the biomarkers including LDH, GGT, KIM-1, clusterin, CysC, NGAL, TIMP-1, GSTπ and osteopontin was evaluated with 22 well characterized compounds. The area under the curve (AUC) values of KIM-1, clusterin, CysC and osteopontin ranged between 0.79 and 0.84. The combination of clusterin, KIM-1 and/or osteopontin improved the AUC value (ranging between 0.88 and 0.95) compared to one biomarker. Taken together, these results suggest that the model based on the HK-2 cell using clusterin, osteopontin, CysC and KIM-1 as endpoints would allow the prediction of nephrotoxicity at early preclinical stages.
研究领域:
毒理学
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药理学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JCI Insight
·
2025
·
IF 6.1
Ping Gao,Xinwei Cheng,Maochang Liu,Hui Peng,Guodong Li,Tianze Shang,Jianqiao Wang,Qianyan Gao,Chenglong Zhu,Zhenpeng Qiu,Chengliang Zhang
Tacrolimus-induced chronic nephrotoxicity (TICN) hinders its long-term use, but its mechanism remains unclear. Tacrolimus exerts its pharmacological effect by inhibiting calcineurin and its substrate NFAT. Whether the inhibition of other calcineurin substrates is related to TICN remains to be explored. Transcription factor EB (TFEB), a substrate of calcineurin, plays a crucial role in various homeostasis. Herein, we found that tacrolimus inhibited TFEB nuclear translocation and activity in mouse kidneys and HK-2 cells. Then, TFEB gain- and loss-of-function rescued the effect of tacrolimus in HK-2 cells. Furthermore, TFEB activation both by phosphorylation sites mutation and agonist rescued TICN in mice. To elucidate the mechanism of TFEB, we analyzed ChIP-seq data. Growth arrest and DNA damage-inducible 45α (GADD45α) was identified as a transcriptional target of TFEB via chromatin immunoprecipitation and dual luciferase reporter assays. And then we revealed that GADD45α overexpression rescued DNA damage and kidney injury caused by tacrolimus or TFEB knockdown in vitro, and vise versa. The protective effect of GADD45α against TICN and DNA damage was further demonstrated by overexpressing it in mice. In conclusion, the persistent inhibition of TFEB-GADD45α pathway by tacrolimus contributes to TICN. This study identifies a specific target for intervention of TICN.
研究领域:
药理学
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肾病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Tongwang Luo,Shengzhe Song,Shujie Wang,Sheng Jiang,Bin Zhou,Quanjiang Song,Lingjun Shen,Xiaodu Wang,Houhui Song,Chunyan Shao
Cadmium (Cd), a pervasive environmental toxicant, poses significant threats to human and animal health through multi-organ toxicity. While ferroptosis has been implicated in Cd-induced pathologies, the molecular mechanisms underlying Cd-mediated nephrotoxicity remain poorly understood. This study elucidates the ferroptosis pathway in CdCl 2 -exposed PK-15 cells and murine kidney, characterized by iron overload, lipid peroxidation, and mitochondrial dysfunction, which were ameliorated by ferroptosis inhibitor ferrostatin-1. Transcriptomic analysis revealed substantial upregulation of heme oxygenase-1 (HO-1) following CdCl 2 exposure. Mechanistically, CdCl 2 triggered nuclear translocation of nuclear factor erythroid 2-related factor-2 (NRF2), subsequently activating HO-1 transcription. Over-activated HO-1 catalyzes the decomposition of heme and releases free iron, accompanied with the degradation of ferritin heavy chain 1 (FTH1) induced by CdCl 2 exposure, which leads to intracellular iron overload and excessive lipid peroxides production through Fenton reaction, resulting in ferroptosis ultimately. In vivo validation confirmed NRF2/HO-1-mediated ferroptosis in CdCl 2 -induced murine nephrotoxicity. Both pre-treatment with HO-1 competitive inhibitor Zinc protoporphyrin IX (ZnPP) and knockout of HO-1 gene remarkably alleviated PK-15 cells against ferroptosis induced by CdCl 2 treatment. Our findings demonstrate that Cd exposure initiates NRF2-mediated HO-1 overexpression, driving iron-dependent lipid peroxidation and subsequent ferroptosis. This mechanistic insight provides potential therapeutic targets for mitigating Cd-induced renal damage, advancing our understanding of heavy metal toxicity and its cellular consequences.
研究领域:
毒理学
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细胞生物学
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环境健康科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY A
·
2024
·
IF 3.8
Xueli Liu,Yuan Luo,Yu Fan,Xiujun Cao,Jun Lu,Guoxin Song,Chunhui Deng
Aristolochic acids (AAs) naturally occurring in the herbal genus Aristolochia are associated with a high risk of kidney failure, multiple tumors and cancers. However, approaches with high selectivity and rapidity for measuring AAs in biological samples are still inadequate. Inspired by the mechanism of AAs-induced nephrotoxicity, we designed a hybrid magnetic polymer-porous agarose (denoted as MNs@SiO 2 M@DNV-A), mimicking the effect of basic and aromatic residues of organic anion transporter 1 (OAT1) for efficient enriching aristolochic acid I (AA I) and aristolochic acid II (AA II) in the plasma. The monomers of vinylbenzyl trimethylammonium chloride (VBTAC), N-vinyl-2-pyrrolidinone (NVP) and divinylbenzene (DVB) were employed to construct the polymer layer, which provided a selective adsorption for AAs by multiple interactions. The porous agarose shell contributed to remove interfering proteins in the plasma samples. A magnetic solid-phase extraction (MSPE) based on the proposed composite enhanced the selectivity toward AA I and AA II in the plasma samples. In combination of HPLC analysis, the proposed method was proved to be applicable to fast and specific quantification of AAs in blood samples, which was characterized by a good linearity, high sensitivity, acceptable recovery, excellent repeatability and satisfactory reusability.
研究领域:
药理学
·
分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2023
·
IF 3.3
Miao Xing,Xiaoyu Ma,Xi Wang,Haoze Wang,Minjuan Xie,Ziwen Zhang,Jie Zhou
Emodin has been demonstrated to possess multiple pharmacological activities. However, emodin has also been reported to induce nephrotoxicity at high doses and with long-term use, and the underlying mechanism has not been fully disclosed. The current study aimed to investigate the roles of oxidative stress and ferroptosis in emodin-induced kidney toxicity. Mice were intraperitoneally treated with emodin, and NRK-52E cells were exposed to emodin in the presence or absence of treatment with Jagged1, SC79, or t-BHQ. Emodin significantly upregulated the levels of blood urea nitrogen, serum creatinine, malondialdehyde, and Fe 2+ , reduced the levels of superoxide dismutase and glutathione, and induced pathological changes in the kidneys in vivo. Moreover, the viability of NRK-52E cells treated with emodin was reduced, and emodin induced iron accumulation, excessive reactive oxygen species production, and lipid peroxidation and depolarized the mitochondrial membrane potential ( ΔΨm ). In addition, emodin treatment downregulated the activity of neurogenic locus notch homolog protein 1 (Notch1), reduced the nuclear translocation of nuclear factor erythroid-2 related factor 2 (Nrf2), and decreased glutathione peroxidase 4 protein levels. However, Notch1 activation by Jagged1 pretreatment, Akt activation by SC79 pretreatment, or Nrf2 activation by t-BHQ pretreatment attenuated the toxic effects of emodin in NRK-52E cells. Taken together, these results revealed that emodin-induced ferroptosis triggered kidney toxicity through inhibition of the Notch1/Nrf2/glutathione peroxidase 4 axis.
研究领域:
药理学
·
毒理学
·
细胞生物学
·
肾脏生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Yonglong Jin,Nina Dong,Shosei Shimizu,Yinuo Li,Yuan Yao,Hong Qiao,Xiguang Liu,Shuai Liu,Chuanlong Guo,Lijie Wang
The incidence rate and mortality rate of breast cancer remain high, and there is an urgent need for safe and effective drugs. The excellent biological activity of hesperidin (HE) is a potential drug for the treatment of breast cancer. In this study, silk fibroin peptides (SFP) were used as delivery carriers and HE loaded SFP nanofibers (SFP/HE NFs) was prepared. The in vitro results showed that SFP/HE NFs significantly inhibited the proliferation and migration of breast cancer cell MDA-MB-231 compared with free HE. The mechanism results demonstrated that SFP/HE NFs induced apoptosis and DNA double stranded damage (DSBs) and further activated the cyclic monophosphate guanosine adenosine monophosphate synthase- stimulator of interferon gene (cGAS-STING) pathway. The in vivo studies showed that SFP/HE NFs treatment significantly inhibited the growth of breast cancer, with an inhibition rate of 65.9 % (100 mg/kg). In vivo mechanism studies also demonstrated that the anti-tumor activity of SFP/HE NFs was related to the activation of the cGAS-STING pathway. Interestingly, we found that the combination of SFP/HE NFs and cisplatin not only enhanced the anti-tumor activity of cisplatin, but also alleviated cisplatin induced nephrotoxicity. In conclusion, our results demonstrate the benefits of activating the cGAS-STING pathway in the treatment of breast cancer, which is expected to provide potential candidates for combined treatment of breast cancer.
研究领域:
药理学
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肿瘤学
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生物材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
GLYCOBIOLOGY
·
2017
·Vol. 27
·期 9
·861-867
·
IF 3.112
Qiu Yuanhao,Hou Yilin,Sun Feifei,Chen Peng,Wang Dongdong,Mu Haibo,Zhang Xiaoli,Ding Kan,Duan Jinyou
Antibiotics such as β-lactams and aminoglycosides are often subtherapeutic to intracellular infections due to their high hydrophilicity, resulting in low effectiveness against intracellular pathogens and the emergence of antibiotic resistance. Here we reported that an endogenous aminoglycan, hyaluronic acid could be an effective carbohydrate carrier of the aminoglycoside antibiotic, streptomycin against intracellular pathogens. This conjugation could enhance phagocytic activity, and facilitated the entry of streptomycin into host cells via a CD44-mediated pathway. It appeared that this conjugate could clear intracellular bacteria in phagocytic or nonphagocytic cells in a short-term therapy (4 h) at a lower effective dose. In addition, this conjugate was more efficient in reducing bacteria burden in an in vivo acute infection model than streptomycin did. Interestingly, subcutaneous injection of this conjugate at an excess amount had undetectable side effects such as nephrotoxicity. These results suggested that hyaluronic acid might be an efficient Trojan horse for the delivery of hydrophilic antibiotics to deal with intracellular infections.
研究领域:
药理学
·
微生物学
·
药物递送系统
✓ 已验证
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）