PHYSIOLOGICAL RESEARCH
·
2024
·Vol. 73
·期 5
·779
·
IF 1.9
Lu BAI,Qian CHEN,Yanqing LI,Fen WU,Mingzhe JIN,Yuhong CHEN,Xu TENG,Sheng JIN,Huanfang FAN,Yuming WU
Trimethylamine N-oxide (TMAO), a bioactive metabolite of gut microbes, plays a pivotal role in the pathogenesis of kidney diseases by activating programmed cell death (PCD) pathways. However, whether trimethylamine (TMA) contributes to chronic kidney injury and which kind of PCD is involved in TMA-induced chronic kidney injury has not been previously evaluated. To observe the effect of TMA, male C57BL/6J mice were randomly divided into two groups: the Control group and the TMA group. The mice in the TMA group were intraperitoneally injected with 100 μmol/kg/day TMA for three months, whereas the mice in the Control group were injected with normal saline for the same period. After three months, plasma creatinine and blood urea nitrogen levels, indicators of kidney function, increased significantly in the TMA group as compared with those in the Control group. Furthermore, Masson staining assay showed that TMA treatment led to a larger area of fibrosis than the Control group. TMA treatment did not change the Bax/Bcl-2 ratio, RIP1, RIP3 and MLKL phosphorylation, or iron and malondialdehyde levels in kidney tissues, indicating that apoptosis, ferroptosis and necroptosis were not involved in TMA-induced chronic kidney injury. However, compared with the Control group, TMA treatment significantly upregulated NLRP3, Caspase-1, IL-1β, cleaved-Caspase 8, Caspase-8, and ZBP1 protein expression in kidney tissues. These results indicated that the ZBP1-NLRP3 inflammasome pathway was involved in TMA-induced chronic kidney injury. In conclusion, our studies revealed that the ZBP1-NLRP3 inflammasome may take part in the progression of TMA induced chronic kidney injury.
研究领域:
肾脏病学
·
免疫学
·
微生物学
·
分子生物学
·
病理学
✓ 已验证
DOI
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2025
·
IF 11.3
Wen Xie,Yajing Zhang,Yu He,Hang Su,Jinni Zhang,Canrong Chen,Peisi Xie,Jing Chen,Zian Lin,Zongwei Cai
Imidacloprid (IMI), a neonicotinoid insecticide extensively applied in agriculture, is among the most frequently detected pesticides in food. However, the long-term impact of chronic dietary exposure to environmentally relevant IMI doses on kidney health has not been fully elucidated, particularly regarding its nephrotoxic mechanisms. To address this gap, chronic exposure to IMI was administered to mice through supplementation of their feed with environmentally relevant doses (approximately 100 and 1000 μg/kg/day) for 24 weeks to investigate its nephrotoxicity and underlying mechanisms. Toxicological analysis revealed that chronic IMI exposure led to renal dysfunction, histopathological alterations, and excessive apoptosis in mice. Mechanistic investigations suggested that IMI might inhibit AMP-activated protein kinase (AMPK) activity through both direct and indirect pathways. Direct inhibition occurred through the binding of IMI and its metabolites to AMPK, reducing its phosphorylation activity. Indirect inhibition involved excessive production of reactive oxygen species, which suppressed AMPK phosphorylation, leading to sustained purine metabolism dysregulation in the renal system. Consequently, the kidneys showed an aggravated redox imbalance, heightened inflammatory states, and increased cellular apoptosis. The results of this study are intended to raise awareness of pesticide use and food safety among agricultural workers and consumers.
研究领域:
毒理学
·
环境科学
·
生物化学
·
药理学
·
食品安全
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYSIOLOGICAL RESEARCH
·
2025
·
IF 2
D Shao,L Bai,Q Chen,Y Chen,Z Qiu,Y Liu,S Jin,Y Wu,J Dai
Trimethylamine N-oxide (TMAO) is involved in the development of kidney disease. However, the specific mechanism by which it leads to kidney injury is unclear. This study explored the role of regulated cell death in TMAO-induced kidney injury. We constructed a TMAO-induced chronic kidney injury model by intraperitoneal injection of TMAO (100 micromol/kg/day for three months). Plasma creatinine (Cre) and urea nitrogen (BUN) levels were measured to evaluate kidney function. Masson staining was used to evaluate kidney pathological changes. The expression levels of regulated cell death-related proteins were measured using western blotting. Plasma Cre and BUN, the area of kidney fibrosis in the TMAO group significantly increased. The western blotting results showed cleaved-Caspase-8, Caspase-8, Caspase-1, NOD-like receptor protein 3 (NLRP3), interleukin-1beta (IL-1beta), cleaved-gasdermin D (cleaved-GSDMD), Z-DNA binding protein 1 (ZBP1), phosphorylation of receptor-interacting protein kinase 3 (RIP3) and mixed-lineage kinase domain-like pseudokinase (MLKL) significantly elevated in the TMAO group. The transferrin receptor 1 (TFR1), ferritin heavy chain (FTH), ferroportin (FPN), nuclear factor erythroid 2-related factor 2 (NRF2), and glutathione peroxidase 4 (GPX4) protein expression in kidney tissue of the TMAO group significantly up-regulated. However, there was no change in iron and MDA levels. The results suggested that PANoptosis, including pyroptosis, apoptosis, and necroptosis components, might be involved in TMAO-induced chronic kidney injury.
研究领域:
肾脏病学
·
细胞生物学
·
分子生物学
·
病理学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Toxicologic Pathology
·
2016
·
IF 0.848
Yuan Yuan,Shixun Ma,Yongmei Qi,Xue Wei,Hui Cai,Li Dong,Yufeng Lu,Yupeng Zhang,Qingjin Guo
The objective of the current study was to explore the inhibitory effects of quercetin on cadmium-induced autophagy in mouse kidneys. Mice were intraperitoneally injected with cadmium and quercetin once daily for 3 days. The LC3-II/β-actin ratio was used as the autophagy marker, and autophagy was observed by transmission electron microscopy. Oxidative stress was investigated in terms of reactive oxygen species, total antioxidant capacity, and malondialdehyde. Cadmium significantly induced typical autophagosome formation, increased the LC3-II/β-actin ratio, reactive oxygen species level, and malondialdehyde content, and decreased total antioxidant capacity. Interestingly, quercetin markedly decreased the cadmium-induced LC3-II/β-actin ratio, reactive oxygen species levels, and malondialdehyde content, and simultaneously increased total antioxidant capacity. Cadmium can inhibit total antioxidant capacity, produce a large amount of reactive oxygen species, lead to oxidative stress, and promote lipid peroxidation, eventually inducing autophagy in mouse kidneys. Quercetin could inhibit cadmium-induced autophagy via inhibition of oxidative stress. This study may provide a theoretical basis for the treatment of cadmium injury.
研究领域:
毒理学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2018
·
IF 4.427
Peng-Cheng Li,Xue-Nan Li,Zheng-Hai Du,Hui Wang,Zhuo-Ran Yu,Jin-Long Li
Di (2-ethyl hexyl) phthalate (DEHP) as a plasticizer can leach away from the plastic and hence entrances into the animal food chain which caused serious hazard in organs of animals, but there are few studies on DEHP kidney toxicity. The heat-shock response (HSR) consisting of the HSPs and HSFs plays an important role in various toxicity stress conditions. To investigate the influence on kidney toxicity and the modulation of HSR during DEHP exposure, female quail were fed the diet with 0, 250, 500 and 750 mg/kg DEHP by gavage administration for 45 days. The shrinkages of glomeruli and dilation of kidney tubule epithelia cells were observed in the kidney of DEHP-exposed quail. DEHP treatment could significantly decrease the expressions of HSP25, HSP27, HSP47, HSP60 , while the expressions of HSP10, HSP40, HSP70, HSP90, HSP110 were upregulated in the kidney. In addition, the expression levels of HSF1 and HSF3 were significantly increased under DEHP. This is the first study to demonstrate quail exposure to DEHP is in fact detrimental to bird kidney. Besides, DEHP could attack HSR by affecting the synthesis of HSFs to mediate the transcription of the HSPs resulting in kidney damage.
研究领域:
毒理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2020
·
IF 6.793
Zhiyuan Meng,Sinuo Tian,Wei Sun,Li Liu,Sen Yan,Shiran Huang,Wentao Zhu,Zhiqiang Zhou
Prothioconazole (PTC), a popular agricultural fungicide , and its main metabolite prothioconazole-desthio (PTCd) are receiving great attention due to their toxicological effects in the non-target organisms. This study investigated their dosage-dependent (1 and 5 mg/kg BW/day) toxicological effects on oxidative stress and metabolic profiles of liver and kidney tissues using male mice. PTC and PTCd significantly inhibited the growth phenotype including body weights gain, liver and kidney indices. Furthermore, these effects were deeply investigated using the biomarkers of oxidative stress, and metabolomics. Notably, these effects were dose and tissue-dependent. Specifically, the more serious impacts involving oxidative stress and metabolic disorders were observed in the high concentration treatment groups. Also, the liver tissue was more severely affected than the kidney tissue. Lastly, the change in oxidative stress biomarkers and metabolomics profile revealed that PTCd induced more severe toxic effects than the parent compound PTC. In brief, these results indicate that exposure to PTC and PTCd could cause potential health risks in mammals.
研究领域:
毒理学
·
环境科学
·
代谢组学
✓ 已验证
DOI
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2024
·
IF 3.4
Zhao Man,Xie Longqiang,Huang Wenbin,Li Meiling,Gu Xin,Zhang Wei,Wei Jintao,Zhang Niya
Cadmium (Cd) and lead (Pb) are heavy metals prevalent in the environment and feed, and they reduce production performance of domestic animals, as well as they result in residue in animal tissues. The kidney is the target tissue for Cd and Pb. And the kidney is crucial for the reabsorption of calcium (Ca), which consequently influences bone strength. However, there are relatively few studies related to the effects of Cd and Pb exposure on performance, bone strength and kidney damage in livestock. The purpose of this experiment was to explore the combined effect of Cd and Pb on growth performance and renal impairment and the possible underlying mechanism. For this, 168 1-day-old Ross 308 broilers were randomly divided into four groups of six birds each, with seven replicates in each group: control group, 50 mg Cd/kg body weight group, 200 mg Pb/kg body weight group and 50 mg Cd/kg body weight + 200 mg Pb/kg body weight group. Feed intake was recorded daily and body weight was recorded weekly. The results show that at the end of the 3rd and 6th week, one broiler from each replicate was randomly selected for sampling. Boilers co-exposed to Cd and Pb for 3 weeks and 6 weeks had significantly decreased average daily feed intake (ADFI) and average daily body weight gain (ADG) than the control group, and the ratio of feed-to-weight gain (F/G) significantly increased after 6 weeks of co-exposure to Cd and Pb. Microscopic picture and ultrastructure analyses of the kidneys showed that Cd and Pb caused kidney damage to broiler chickens, and the damage was more serious in the Cd + Pb group, which was manifested by increased renal tubular epithelial degeneration and increased interstitial stasis points. Dietary exposure to Cd and Pb impaired production performance and induced renal oxidative damage in broilers. The combined effects of Cd and Pb on the kidneys are greater than their effects alone. The PERK-ATF4 pathway mediated endoplasmic reticulum stress participates the renal oxidative damage during chronic Cd and Pb exposure.
研究领域:
动物科学
·
毒理学
·
营养学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Yi Cai,Liduan Huang,Yanhong Hou,Peiwen Pang,Ying Zhou,Xuan Zhang,Yiyin Long,Huajian Li,Halimulati Muhetaer,Man Zhang,Bo Wu
Andrographolide, a diterpene compound derived from the medicinal plant Andrographis paniculata , possesses anti-inflammatory, antioxidant, antitumor, and antiviral properties. Injectable formulations containing andrographolide, such as Potassium Sodium Dehydroandrographolide Succinate for Injection (PSDS), are widely used in clinical practice to treat various diseases, including upper respiratory tract infections. However, clinical reports have highlighted that andrographolide-based herbal injections may induce acute kidney injury and other renal adverse effects, thereby restricting its clinical application. Despite these concerns, the molecular mechanisms underlying andrographolide-induced nephrotoxicity remain poorly understood. In this study, we demonstrated that andrographolide induces inflammation and fibrosis in renal tubular epithelial cells and mouse kidneys. Notably, we identified for the first time that andrographolide promotes cellular senescence in renal tubular epithelial cells and mouse kidneys while downregulating the expression and enzymatic activity of SIRT3. Mechanistic investigations revealed that andrographolide mediates kidney injury and senescence through inhibition of the SIRT3/p53 signaling pathway. Furthermore, andrographolide was found to disrupt the interaction between SIRT3 and p53, resulting in increased acetylation of p53 and upregulation of its downstream target genes involved in inflammation, fibrosis, and senescence. These findings elucidate the molecular mechanisms of andrographolide-induced nephrotoxicity and provide a scientific basis for developing strategies to reduce its toxic effects.
研究领域:
药理学
·
分子生物学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INORGANIC CHEMISTRY
·
2025
·
IF 4.7
Jingwen Guan,Xiaomei Wang,Yemeng Chen,Hailong Zhang,Zongyi Li,Ao Li,Fuwan Zhai,Lanhua Chen,Lei Chen,Ximeng Li,Bin Chen,Yigong Xu,Xiao Dong,Wei Liu,Xing Dai,Shuao Wang,Juan Diwu
The internal contamination of uranium poses severe health risks to both professionals and the public in case of nuclear accidents due to its chemo- and radiotoxicity. Although chelation therapy has been considered the only practical treatment in emergencies, current clinical chelators show only limited efficacy for uranium. Herein, a recently designed lacunary selenotungstate polyoxometalate (Se6W45) was demonstrated as an effective therapeutic agent. In this construct, the open site in Se6W45 provides a suitable uranium binding environment, resulting in the selective removal of uranium from kidneys (85.87%) and femurs (39.81%) with an extremely low ligand/metal ratio of only 4:1. The redox active sites in Se6W45, primarily the incorporated selenium, were able to reduce the intracellular reactive oxygen species (ROS) to normal levels in NRK-52E cells exposed to uranium. This approach overcomes the disadvantages of the excessive use of current chelating ligands in the range from 100- to 1000-folds, avoiding the consequential depletion of heterogeneous cations, dysfunction of proteins, and/or acid–base imbalance. More importantly, it provides a synergistic antidotal therapy for uranium in reducing radiation damage and chemical toxicity.
研究领域:
放射生物学
·
毒理学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
VETERINARY RESEARCH COMMUNICATIONS
·
2025
·Vol. 49
·期 5
·1-10
·
IF 2
Liu Shuang,Qiu Bo,Li Yue,Wang Hai-Peng,Zhong Zhao-Jin,Wang Lin
Glyphosate (Gly) is a globally prevalent herbicide, which poses significant health risks to human and animals via the food chain. The kidney is the primary excretory organ and a site of residual accumulation during Gly exposure. Trehalose (Tre) has been shown to prevent kidney injury induced by various toxicants due to its anti-apoptotic properties. However, the potential protective effect of Tre on Gly-induced kidney damage in poultry remains unclear. Thus, 60 one-day-old healthy Hy-line Brown roosters were randomly divided into three groups ( n = 20), i.e., control group (basal diet without Gly), Gly group (200 mg Gly/kg basal diet), and Gly + Tre group {(200 mg Gly plus 5 g Tre)/kg basal diet}. The experiment lasted for 120 days, and serum and kidney samples were finally collected for respective analysis. Data first showed that Tre treatment can significantly alleviate Gly-induced renal injury in roosters, as evidenced by serum levels of creatinine and blood urea nitrogen as well as renal histopathological observations. Tre also significantly inhibited the elevated abundance of renal injury marker proteins KIM-1 and NGAL induced by Gly. Meanwhile, Tre obviously alleviated Gly-induced ultrastructural abnormalities in the nuclei of renal tissues. Additionally, Tre markedly inhibited Gly-induced apoptotic assays in rooster kidneys, as demonstrated by the results from TUNEL staining and the protein abundance of apoptotic markers cleaved caspase-3 and cleaved PARP. In summary, these findings suggest that Tre exerts its protective effects against Gly-induced kidney damage in roosters via inhibiting apoptosis.
研究领域:
毒理学
·
兽医学
·
分子生物学
·
环境卫生
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Ying Li,Zhi-Hao Ma,Xiao Liu,Wenting Zhu,Long Chen,Wanyi Xu,Lei Wang,Jingquan Dong,Zi-Bo Dong
Higenamine Hydrochloride (HGN) is an alkaloid derived from the traditional Chinese medicinal herb Aconite, possesses pharmacological activities such as anti-inflammatory and antioxidant properties. Its specific role in diabetic nephropathy (DN) remains unknown. The purpose of this work was to investigate the protective impact of HGN against streptozotocin (STZ)-induced renal inflammation and fibrosis in DN mice, as well as to investigate its probable mechanism of action in vitro using high glucose (HG)-treated HK-2 cells. We constructed a mouse model of DN by intraperitoneal injection of STZ and a HK-2 cell model using HG treatment, followed by administration of HGN. Tissue distribution experiments, biochemical analysis, real-time PCR, immunoblotting, and histopathological examination were used to assess the effects of HGN on renal histopathology, inflammation, and fibrosis in DN mice and its molecular mechanisms. The results demonstrated that in the renal tissues of DN mice, HGN had the highest concentration. HGN treatment led to body weight increase, and blood glucose levels fell as well as the improvement in metabolic abnormalities. It further proved that HGN alleviated renal function damage by lowering serum creatinine (SCr), blood urea nitrogen (BUN), cystatin C (Cys-C), and renal index values. Moreover, HGN improved kidney histopathology, reduced renal tubular damage, and decreased interstitial inflammation. The kidneys had less collagen accumulation. At the same time, HGN decreased the expression of markers associated with inflammation (iNOS, IL-1β, IL-6, MCP-1) and fibrosis (Collagen-I, MMP9, α-SMA, CTGF). Mechanistic studies have shown that, in vitro, HGN inhibits STAT3 phosphorylation, thereby inhibiting the expression of inflammatory (iNOS, IL-1β, IL-6, and MCP-1) and fibrosis-related cytokines (Collagen-I, MMP9, α-SMA, and CTGF) in HK-2 cells under HG conditions. To summarize, HGN inhibits renal inflammation and fibrosis in DN mice by inhibiting the STAT3 pathway, and this discovery offers a new possible target for DN treatment.
研究领域:
药理学
·
传统中医药
·
分子生物学
·
病理学
·
生物化学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FASEB JOURNAL
·
2025
·Vol. 39
·期 14
·e70861
·
IF 4.2
Ke Sun,Fugang Huang,Wenjin Xie,Wenbo Hu,Mengting Zhu,Zhenliang Fan,Keda Lu
Chronic kidney disease (CKD) is a significant global health issue, and effective treatments are limited. Xiaoyu Xiezhuo Decoction (XYXZD), a traditional Chinese medicine, has shown potential in modulating the gut–kidney axis and related signaling pathways. This study investigates the effects of XYXZD in alleviating tubulointerstitial fibrosis (TIF) in a unilateral ureteral obstruction (UUO) rat model by targeting the aldosterone (ALD)/mineralocorticoid receptor (MR)/serum- and glucocorticoid-inducible kinase-1 (SGK-1) signaling pathway and exploring the role of butyrate. UUO rats were divided into four groups: control, UUO model, XYXZD treatment, and irbesartan treatment. Renal function was assessed by measuring serum creatinine (Scr), blood urea nitrogen (BUN), and ALD levels. Fibrosis markers, including alpha-smooth muscle actin (α-SMA) and Collagen Type III (COL-III), as well as signaling molecules such as phosphorylated SGK-1 (p-SGK-1) and phosphorylated nuclear factor kappa B (p-NF-κB), were analyzed by Western blot and immunohistochemistry. Gut microbiota composition was evaluated using 16S ribosomal DNA (rDNA) sequencing, and the role of butyrate was examined via oral gavage treatment. XYXZD significantly improved renal function, reduced fibrosis, and restored gut microbiota balance by increasing butyrate-producing bacteria. XYXZD also reduced serum ALD levels and inhibited SGK-1 phosphorylation, suggesting modulation of the ALD/MR signaling pathway. Furthermore, butyrate treatment reduced MR nuclear translocation, supporting its role in the therapeutic effects of XYXZD. XYXZD alleviates renal injury in UUO rats by modulating the gut–kidney axis, particularly through the ALD/MR/SGK-1 signaling pathway, with butyrate playing a critical role. These findings highlight a promising approach for CKD treatment by targeting gut microbiota and enhancing butyrate production. Graphical Mechanism of XYXZD improvement of renal injury through modulation of the gut–kidney axis and ALD/MR/SGK-1 signaling pathway.
研究领域:
药理学
·
肾脏病学
·
微生物学
·
中医学
·
分子生物学
✓ 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）