CHEMOSPHERE
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2017
·
IF 4.208
Jie Zhang,Tiehua Zhang,Tianzhu Guan,Ping Ruan,Dayong Ren,Weichang Dai,Hansong Yu,Tiezhu Li
A fluorescence polarization (FP) assay for the simultaneous determination of bisphenol A (BPA), bisphenol F (BPF), bisphenol A diglycidyl ether (BADGE) and bisphenol F diglycidyl ether (BFDGE) was developed. The method was based on the competition between bisphenols (BPs) and fluorescein-labeled dexamethasone derivative (Dex-fl) for mouse peroxisome proliferator-activated receptor α ligand binding domain (mPPARα-LBD). A recombinant soluble protein derivative mPPARα-LBD* was prepared, then in vitro binding of 4 BPs to mPPARα-LBD* was investigated. Fluorescence polarization assay showed that these compounds exhibited different binding potencies with mPPARα-LBD*. Additionally, molecular dynamics simulations were performed to further understand the mechanism of BPs binding affinity for mPPARα-LBD*. Docking results elucidated that the driving forces for the binding of BPs to mPPARα-LBD* were predominantly dependent on hydrophobic and hydrogen-bonding interactions. Comparison of the calculated binding energies vs. experimental binding affinities yielded a good correlation (R 2 = 0.7258). The proposed method has potential for multi-residue detection of BPA, BPF, BADGE, and BFDGE.
研究领域:
生物化学
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环境科学
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毒理学
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DOI
PubMed
高影响因子
Analytical Methods
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2015
·Vol. 8
·期 4
·880-885
·
IF 1.821
Jie Zhang,XiaoJia Xing,Yonghai Sun,Zhuolin Li,Peiyu Xue,Tuoyi Wang,Tiezhu Li
The binding of phthalate esters (PAEs) to peroxisome proliferator-activated receptor α (PPARα) has been investigated by using fluorescence polarization (FP) in combination with molecular modeling techniques. The FP competitive binding assay is based on a mouse-derived recombinant PPARα ligand binding domain (LBD) and a fluorescent-labeled fatty acid (C4-BODIPY-C9). A soluble mPPARα-LBD protein derivative, named mPPARα-LBD*, was expressed and purified. By using C4-BODIPY-C9 as a probe, 10 common PAEs with different carbon chain lengths and functional groups were assessed for their binding affinities with mPPARα-LBD*, respectively. PAEs displace the probe from the C4-BODIPY-C9–mPPARα-LBD* complex, resulting in lower polarization values. FP assay showed that PAEs compete for the C4-BODIPY-C9 binding sites in a concentration-dependent manner, and the potency of the tested PAEs increases with increasing side chain length. Molecular docking suggested that the length and hydrophobicity of the side chain of PAEs have contributed a lot to the ligand–receptor binding, and there are four prominent interactions observed to stabilize the PAEs–mPPARα-LBD* binding. In addition, comparison of docking scores vs. experimental binding affinities yielded a good correlation (R2 = 0.948). The most active DEHP (Kd = 19.6 ± 1.7 μM) has the lowest ranking on docking scores. The fluorescence polarization-based competitive binding assay can potentially be used for high-throughput screening of PAEs, which may serve as an assistant of chromatographic techniques.
研究领域:
分子生物学
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毒理学
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环境科学
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药物研发
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产品关联
DOI
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2022
·
IF 5.572
Yue-Qiang Huang,Yi-Xi Tang,Bai-Hao Qiu,Milton Talukder,Xue-Nan Li,Jin-Long Li
Di-2-ethylhexyl phthalate (DEHP) has been widely used in many fields (agricultural products, medical instruments, and food packing). As an environmental contaminant, DEHP has a negative impact on human and animal health, and thus toxicity caused by DEHP is increasingly serious health concern. Nevertheless, DEHP-induced liver damage in quail remains unclear. To investigate the mechanism of liver damage caused by DEHP, male quail were treated with DEHP (250, 500, and 750 mg/kg) by gavage. Notably, DEHP exposure results in increased blood lipids and the accumulation of triglycerides (TG), total cholesterol (TC), and non-esterified fatty acid (NEFA) in the liver. Histopathological analysis showed that steatosis and inflammatory cell infiltration were observed in the liver tissue of quails exposed to DEHP. The results of Oil Red O staining displayed that DEHP induced lipid storage in the liver. Moreover, DEHP induced lipid metabolism disorders by activating the LXR / SREBP-1c and PPARα / γ signaling pathway. DEHP exposure obviously caused the up-regulation of pro-inflammatory cytokines ( NF-κB , IL-6 , IL-8 , IL-1β , and TNF-a ). This study showed that DEHP could induce lipid metabolism disorders and inflammatory response via LXR / SREBP-1c / PPARα / γ and NF-κB signaling pathways.
研究领域:
毒理学
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环境健康
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2025
·Vol. 15
·期 1
·1-12
·
IF 3.9
Wan Meixia,Li Qing,Xiao Yudie,Zhou Dan,Lei Qianya,Wang Shu
Mori Fructus, rich in polysaccharides and polyphenols, has long been used in East Asia as a functional food and medicinal agent. In traditional Chinese medicine, it is used to treat various ailments like wasting-thirst syndrome and constipation. Studies suggest its extract fractions may alleviate metabolic syndrome symptoms by affecting gut microbiota. To explore this, fecal microbiota transplantation (FMT) was used in an experiment. Pseudo-germ-free mice were created with antibiotics and given a high-fat, high-sugar diet (HFD) to induce metabolic syndrome. Then, fecal bacterial infusions were transplanted. Results showed significant improvement in metabolic syndrome parameters in the FMT-MFPS(fecal microbiota transplantation-Mori Fructus polyphenols plus polysaccharides) group. Dyslipidemia, liver, and kidney injuries were modulated in treated mice. The PPARα/PGC-1α signaling pathway was activated. These findings indicate Mori Fructus extract fractions prevent metabolic syndrome via gut microbiota modulation, with effects sustained through FMT, providing a reference for prevention.
研究领域:
药理学
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营养学
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微生物学
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代谢性疾病
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中医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2024
·Vol. 13
·期 9
·1026
·
IF 6
Dajin Pi,Zheng Liang,Jinyue Pan,Jianwei Zhen,Chuiyang Zheng,Wen Fan,Qingliang Song,Maoxing Pan,Qinhe Yang,Yupei Zhang
Nonalcoholic steatohepatitis (NASH) is a critical stage in the progression of nonalcoholic fatty liver disease (NAFLD). Tanshinone IIA (TIIA) is a tanshinone extracted from Salvia miltiorrhiza; due to its powerful anti-inflammatory and antioxidant biological activities, it is commonly used for treating cardiovascular and hepatic diseases. A NASH model was established by feeding mice a methionine and choline-deficient (MCD) diet. Liver surface microblood flow scanning, biochemical examination, histopathological examination, cytokine analysis through ELISA, lipidomic analysis, transcriptomic analysis, and Western blot analysis were used to evaluate the therapeutic effect and mechanism of TIIA on NASH. The results showed that TIIA effectively reduced lipid accumulation, fibrosis, and inflammation and alleviated endoplasmic reticulum (ER) stress. Lipidomic analysis revealed that TIIA normalized liver phospholipid metabolism in NASH mice. A KEGG analysis of the transcriptome revealed that TIIA exerted its effect by regulating the PPAR signalling pathway, protein processing in the ER, and the NOD-like receptor signalling pathway. These results suggest that TIIA alleviates NASH by activating the PPARα/FGF21 axis to negatively regulate the ER stress-induced unfolded protein response (UPR).
研究领域:
药理学
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肝病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2024
·
IF 7.1
Chaojuan Wen,Xinyue Yu,Jingya Zhu,Jingshu Zeng,Xielan Kuang,Youao Zhang,Shiyu Tang,Qingjiong Zhang,Jianhua Yan,Huangxuan Shen
Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the elderly, is primarily characterized by the degeneration of the retinal pigment epithelium (RPE). However, effective therapeutic options for dry AMD are currently lacking, necessitating further exploration into preventive and pharmaceutical interventions. This study aimed to investigate the protective effects of gastrodin on RPE cells exposed to oxidative stress. We constructed an in vitro oxidative stress model of 4-hydroxynonenal (4-HNE) and performed RNA-seq, and demonstrated the protective effect of gastrodin through mouse experiments. Our findings reveal that gastrodin can inhibit 4-HNE-induced oxidative stress, effectively improving the mitochondrial and lysosomal dysfunction of RPE cells. We further elucidated that gastrodin promotes autophagy and phagocytosis through activating the PPARα-TFEB/CD36 signaling pathway. Interestingly, these outcomes were corroborated in a mouse model, in which gastrodin maintained retinal integrity and reduced RPE disorganization and degeneration under oxidative stress. The accumulation of LC3B and SQSTM1 in mouse RPE-choroid was also reduced. Moreover, activating PPARα and downstream pathways to restore autophagy and phagocytosis, thereby countering RPE injury from oxidative stress. In conclusion, this study demonstrated that gastrodin maintains the normal function of RPE cells by reducing oxidative stress, enhancing their phagocytic function, and restoring the level of autophagic flow. These findings suggest that gastrodin is a novel formulation with potential applications in the development of AMD disease.
研究领域:
眼科学
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药理学
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细胞生物学
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分子生物学
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神经科学
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DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2024
·
IF 2.9
Yifei Zhang,Jie Yang,Shicheng Fan,Yue Gao,Chenghui Cai,Huilin Li,Xuan Li,Xiao Yang,Yunhui Xing,Min Huang,Huichang Bi
The activation of pregnane X receptor (PXR) or peroxisome proliferator-activated receptor α (PPARα) can induce liver enlargement. Recently, we reported that PXR or PPARα activation-induced hepatomegaly depends on yes-associated protein (YAP) signaling and is characterized by hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. However, it remains unclear whether PXR or PPARα activation-induced hepatomegaly can be reversed after the withdrawal of their agonists. In this study, we investigated the regression of enlarged liver to normal size following the withdrawal of PCN or WY-14643 (typical agonists of mouse PXR or PPARα) in C57BL/6 mice. The immunohistochemistry analysis of CTNNB1 and KI67 showed a reversal of hepatocyte size and a decrease in hepatocyte proliferation after the withdrawal of agonists. In details, the expression of PXR or PPARα downstream proteins (CYP3A11, CYP2B10, ACOX1, and CYP4A) and the expression of proliferation-related proteins (CCNA1, CCND1, and PCNA) returned to the normal levels. Furthermore, YAP and its downstream proteins (CTGF, CYR61, and ANKRD1) also restored to the normal states, which was consistent with the change in liver size. These findings demonstrate the reversibility of PXR or PPARα activation-induced hepatomegaly and provide new data for the safety of PXR and PPARα as drug targets.
研究领域:
药理学
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肝病学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Chinese Herbal Medicines
·
2026
·
IF 11.2
Fanghong Li,Xiaojiaoyang Li,Yajie Cai,Yufei Li,Yang Yang,Jianan Li,Ruiyu Wu,Ranyi Luo,Rong Sun,Runping Liu
Objective To investigate the therapeutic effects of Sini San (SNS) in cholestatic mice, and to elucidate underlying mechanisms and bioactive ingredients. Methods Through a metabolomics approach, this study identified bioactive components in SNS that were absorbed into the bloodstream. Transcriptomics were performed to identify intrahepatic targets of SNS. Results These findings demonstrated that SNS significantly attenuated partial bile duct ligation (pBDL)-induced cholestatic liver injury by activating intrahepatic (peroxisome proliferator-activated receptor alpha, PPAR α ). SNS-mediated PPAR α activation significantly modulated the expression of bile acid transporters to facilitate intrahepatic bile acid homeostasis and simultaneously ameliorates hepatic inflammation. This study identified marmin, astilbin, poncirin, and isosinensetin as potential PPAR α agonists among absorbed SNS components. Subsequently, PPAR α inhibitor (GW6471), significantly abolished the regulative effects of SNS on lipid and bile acid metabolism. Conclusion This research not only underscores the regulative role of PPAR α in bile acid metabolism but also indicates the presence of potential PPAR α agonists in SNS, offering a novel therapeutic strategy for treating cholestatic liver disease.
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产品关联
DOI
高影响因子
Liver Research
·
2026
·
IF 4.3
Hang-Fei Liang,Chuo-Ying Mai,Xuan Li,Jia-Ning Tian,Hai-Guo Su,Min Huang,Jian-Hong Fang,Hai-Tao Wang,Xiao Yang,Hui-Chang Bi
Background and aims The mechanism of cholestatic liver injury (CLI) is unclear, and effective therapies are lacking. While peroxisome proliferator-activated receptor alpha (PPARα) agonists show potential hepatoprotective effect and pyroptosis is implicated in hepatocellular damage, how PPARα activation mitigates lithocholic acid (LCA)-induced pyroptosis remains unknown. Methods The hepatoprotective effect of PPARα agonists was evaluated in a mouse model of intrahepatic cholestasis induced by LCA. Liver injury was assessed via serum biochemistry, hematoxylin and eosin and TUNEL staining, and electron microscopy. Pyroptosis pathways were analyzed using real-time quantitative polymerase chain reaction, Western blot, and co-immunoprecipitation. Results Combined morphological, histopathological, and biochemical analyses confirmed that PPARα activation protects against CLI. Compared with LCA treatment alone, PPARα activation significantly attenuated the elevation of serum lactate dehydrogenase (LDH), the increased TUNEL-positive cells, and the formation of hepatocyte membrane pores. Mechanistically, PPARα activation suppressed both NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis and apoptosis protease-activating factor-1 (APAF-1)/CASPASE-3/GSDME-mediated pyroptosis. Furthermore, PPARα agonist pretreatment inhibited activation of the nuclear factor-kappa B (NF-κB) and forkhead box O1 (FOXO1) signaling pathways. Conclusions PPARα protects against LCA-induced CLI by inhibiting both NLRP3 inflammasome-mediated pyroptosis associated with NF-κB and APAF-1/CASPASE-3/GSDME-mediated pyroptosis associated with the FOXO1 signaling pathway.
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DOI
PubMed
高影响因子
Journal of Clinical and Translational Hepatology
·
2026
·Vol. 14
·期 3
·291
·
IF 6
Lingjian Zhang,Yaqi Zhang,Yalei Zhao,Danhua Zhu,Qian Li,Qiuhong Liu,Qingqing Hu,Xiaoxi Ouyang,Lanjuan Li
Background and Aims Acute liver failure (ALF) is a severe hepatic injury associated with high short-term mortality. Our previous study found that 1,5-anhydroglucitol (1,5AG) levels correlate with clinical outcomes in patients with liver failure. This study aimed to explore the potential effects and mechanisms of 1,5AG in ALF. Methods An experimental model of ALF was established using LPS and D-GalN. 1,5AG was administered to mice by gavage before modeling. Empagliflozin was then administered to reduce 1,5AG levels in mice. Peroxisome proliferator-activated receptor alpha (PPARα) agonists were also used to explore the role of 1,5AG in mice with liver failure. Results 1,5AG pretreatment significantly increased ALT and AST levels, aggravated histological damage and hepatocyte apoptosis, and increased mortality in ALF mice. Transcriptomic analysis and western blot validation revealed that 1,5AG significantly inhibited the PPARα signaling pathway and its downstream target, fibroblast growth factor 21. Empagliflozin treatment reduced 1,5AG levels, alleviated liver injury and hepatocyte apoptosis, and promoted the PPARα signaling pathway in ALF. PPARα agonists effectively reversed the effects of 1,5AG on ALF, thereby alleviating liver damage, pathological injury, and hepatocyte apoptosis. Conclusions 1,5AG exacerbated liver injury in ALF mice by inhibiting the hepatic PPARα pathway, thereby promoting hepatocyte apoptosis.
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DOI
PubMed
高影响因子
FOOD RESEARCH INTERNATIONAL
·
2025
·
IF 8
Linlin He,Lan Zhang,Fanyi Meng,Jingge Wei,Fei Chen,Siqi Qin,Ge Jin,Hailong Cao
Intestinal senescence, often characterized by increased oxidative stress, is linked to gastrointestinal disorders such as inflammatory bowel disease and colorectal cancer. While previous studies have suggested that diets rich in food additives, such as the emulsifier Polysorbate 80 (P80), may influence gut health, the impact of P80 exposure on intestinal senescence remains unclear. This study aimed to explore the effects of P80 on intestinal senescence in a senescence-accelerated mouse prone model. The results revealed that P80 exposure could damage the intestinal barrier, induce oxidative stress, and accelerate intestinal senescence. Mechanistically, P80 activated the peroxisome proliferator-activated receptor-α (PPARα) and fatty acid-binding protein 1 (FABP1) axis, increasing intestinal fatty acid absorption and triggering lipotoxicity, which promoted senescence. Additionally, P80 exacerbated D-galactose-induced epithelial cell senescence and lipid accumulation via the PPARα signalling pathway. Importantly, the PPARα antagonist GW6471 mitigated fatty acid uptake and reduced senescence in the intestine. In conclusion, the emulsifier P80 accelerated intestinal senescence by regulating the PPARα-FABP1 axis to induce intestinal fatty acid uptake and lipotoxicity, suggesting new insights into the adverse effects of food additives on gut health.
研究领域:
营养学
·
分子生物学
·
胃肠病学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2025
·
IF 11.3
Qi Jiang,Donghui Zhang,Naifan Hu,Yunfei Ma,Huibin Jin,Yunhao Zhao,Ming Zhang,Bin Li,Zhenzhen Huang,Bifeng Yuan,Ying Zhu,Jianbo Tian,Xiaoping Miao
Screening environmental pollutants that are harmful to the cardiometabolic status and understanding their key toxic pathways are crucial for effective clinical intervention. Based on exposure data of 46 chemicals in a nationally representative 13,286 people, logistic regression and mixture modeling were used to preliminarily identify environmental pollutants with significant impacts on 12 indicators for cardiometabolic disorders. A total of 15 chemicals were found to be associated with the integrated latent class, among which four chemicals (perfluorononanoic acid [PFNA], perfluorooctanoic acid [PFOA], thiocyanate, and thallium) also contributed significantly to the mixture effect. We constructed the adverse outcome pathways (AOPs) for nine significant toxicants in both models of individual chemicals and the mixture for each cardiometabolic disorder. Notably, fluoroalkyl substances affect multiple aspects of hyperlipidemia by activating PPARα. We performed molecular docking and in vitro experiments to verify and supplement the toxicological mechanism of PFNA. Through binding to PPARα, PFNA increased the levels of downstream molecules including CD36 (fatty acid transfer), ACSL1 (fatty acid activation), and CPT1a (intracellular transfer for β-oxidation) and ultimately promoted the accumulation of triglycerides and lipid droplets in HepG2 cells. These markers, together with key events for other metabolic phenotypes, may be potential targets for scientific research or clinical treatment.
研究领域:
环境医学
·
毒理学
·
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）