SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
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IF 8.2
Yang Yang,Yue Tao,Rongyi Yang,Xiaodong Yi,Guanyu Zhong,Yanyan Gu,Ying Zhang
Widespread application of the typical phthalate plasticizers , di (2-ethylhexyl) phthalate (DEHP), poses a serious potential threat to the health of animals and even humans. Previous studies have confirmed the mechanism of DEHP-induced cardiac developmental defects in zebrafish larvae. However, the mechanism of cardiac dysfunction is still unclear. Thus, this work aimed to comprehensively investigate the mechanisms involved in DEHP-induced cardiac dysfunction through computational simulations, in vivo assays in zebrafish, and in vitro assays in cardiomyocytes. Firstly, molecular docking and western blot initially investigated the activating effect of DEHP on Pparg in zebrafish. Although GW9662 (PPARG antagonist) effectively alleviated DEHP-induced cardiac dysfunction and lipid metabolism disorders, it did not restore significant decreases in mitochondrial membrane potential and ATP levels. In vitro assays in cardiomyocytes, DEHP caused overexpression of PPARG and proteins involved in the regulation of Ca 2+ homeostasis , and the above abnormalities were effectively alleviated by GW9662, suggesting that the Ca 2+ homeostatic imbalance caused by activation of PPARG by DEHP seems to be the main cause of DEHP-induced cardiac dysfunction. To sum up, this work not only refines the mechanism of toxic effects of cardiotoxicity induced by DEHP, but provides an important theoretical basis for enriching the toxicological effects of DEHP.
研究领域:
毒理学
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心脏病学
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分子生物学
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发育生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2024
·
IF 10.8
Qian Liu,Xiaoxun Lu,Ganzhong Liao,Fuhui Yan,Miaoliang Wu,Zhi Bai,Huanwen Tang,Xiaoshan Liu
Triphenyl phosphate (TPhP) is a widely used organophosphate flame retardant, the health risks of TPhP are a global concern. In this study, we found that prenatal TPhP exposure at human relevant concentration induced hyperlipidemia in male offspring, it increased serum levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol. Placental trophoblast-derived extracellular vesicles (T-EVs) could transport to the fetus through maternal-fetal circulation. TPhP significantly upregulated the protein level of peroxisome proliferator activated receptor γ (PPARγ) in T-EVs. Similar to TPhP, gestational exposure to T-EVs isolated from TPhP exposed mice placentae induced the same effects. While, gestational intervention with GW9662 (PPARγ inhibitor) or GW4869 (EVs secretion inhibitor) would alleviate the disturbed lipid metabolism induced by TPhP. Meanwhile, in vitro experiments verified that TPhP upregulated PPARγ in HTR8/SVneo cells derived EVs, and these EVs promoted adipogenesis in preadipocyte 3T3-L1 cells. Knock down of PPARγ in HTR8/SVneo could alleviate the adipogenensis effects of EVs derived from TPhP exposed HTR8/SVneo cells. These results demonstrate that TPhP exposure induces hyperlipidemia in male offspring by upregulating PPARγ in T-EVs. Our study provides new insights into the metabolic disruptive effects of TPhP, and emphasizes the mediating effects of placental T-EVs on gestational environmental stress in fetal development.
研究领域:
环境健康
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发育生物学
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代谢
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毒理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2022
·
IF 6.656
Shuang Luo,Jinrong He,Shaowei Huang,Xiaojing Wang,Yulin Su,Yanyang Li,Yanping Chen,Guanghua Yang,Bin Huang,Shaoju Guo,Lian Zhou,Xia Luo
Background Emodin is an active ingredient of traditional Chinese medicine Rheum palmatum L. and Polygonum cuspidatum , which possesses anti-inflammatory and intestinal mucosal protection effects. Our previous study found that emodin significantly alleviated ulcerative colitis induced by sodium dextran sulfate (DSS). In this study, we found the underlying mechanism of emodin on ulcerative colitis (UC). Purpose We aimed to further explore the mechanism of emodin in the treatment of ulcerative colitis from the perspective of metabolism and intestinal flora . Methods Ulcerative colitis was induced by 3% sodium dextran sulfate (DSS) on mice, and the mice were respectively treated with mesalazine , rosiglitazone , emodin, and emodin combined with GW9662 (PPARγ inhibitor) simultaneously. Weight changes , the disease activity index (DAI), colonic length, and pathologic changes in colon were used to evaluate the efficacy of emodin. LC-MS/MS was performed for metabolomics analysis of colon. In addition, intestinal flora was assessed using 16S rDNA sequencing. A vector-based short hairpin RNA (shRNA) method was used to silence PPARγ gene expression in Caco-2 cells. Results Emodin binds to the active site of PPARγ protein and forms hydrogen bond interaction with ARG288 and CYS285 amino acids. Furthermore, Emodin significantly promotes the protein expression of PPARγ, while inhibiting iNOS and NF-kB p65 in UC mice, however, this effect is hardly shown when it is combined with GW9662 (the inhibitor of PPARγ). Meanwhile, emodin suppresses the expression of iNOS in Caco-2 cells induced with IFNγ and IL-22, but has no effect on its expression in shPPARγ-Caco-2 cells. In addition, through activating PPARγ signal pathway , emodin is capable of regulating colonic metabolism including oxidative phosphorylation and citrulline metabolism and effecting luminal availability of oxygen and nitrate. This promotes the recovery of anoxic environment of colon epithelial cells, which strains the growth and expansion of Enterobacteriaceae . Conclusion The mechanism of Emodin in the treatment of ulcerative colitis relies on its regulation of PPARγ signal pathway, which could modulate colonic metabolism and restore intestinal homeostasis .
研究领域:
药理学
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胃肠病学
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分子生物学
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免疫学
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微生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2022
·
IF 9.988
Jiabin Hong,Mengzhu Jiang,Lihao Guo,Juntong Lin,Yao Wang,Huanwen Tang,Xiaoshan Liu
The health risks of triphenyl phosphate (TPhP) have increased since its widespread application. Using placental trophoblast cell line JEG-3, we demonstrated that TPhP could induce endoplasmic reticulum stress (ERS) and cell apoptosis through PPARγ-mediated lipid metabolism . However, the developmental toxicity of TPhP through the placenta is not known. In this study, prenatal TPhP exposure to mice was investigated. Pregnant mice were orally exposed to TPhP (1 and 5 mg/kg) from embryonic day 0 (E0) until delivery. The results showed that TPhP could accumulate in placenta and impair pregnancy outcomes. After exposure, at E18, placental hormone chorionic gonadotrophin and testosterone levels were significantly decreased, but progesterone and estradiol levels were significantly increased, and placental angiogenesis was activated in the low-dose exposure group. While, in the high-dose exposure group, only estradiol levels were significantly increased. Different with the effect on hormone level or angiogenesis, TPhP significantly increased PPARγ and its regulated lipid transport proteins FABP, FATP, and CD36, and induced lipid accumulation in placental trophoblasts of both low- and high-exposure group. RNA-seq analysis of the placenta identified differentially expressed genes that were mainly involved in the ERS and MAPK signaling pathways. Western blot analysis verified that the protein levels related to ERS stress and apoptosis were significantly increased. To further confirm the role of PPARγ in TPhP mediated placental toxicity, pregnant mice were orally exposed to TPhP (1 mg/kg) or TPhP (1 mg/kg) + GW9662 (PPARγ inhibitor, 2 mg/kg) from E0 until delivery. The results showed that GW9662 could ameliorate the effect of TPhP on placental lipid accumulation, ERS and cell apoptosis, suggesting that PPARγ mediated the placental toxicity of TPhP. Overall, our results indicated that prenatal TPhP exposure impaired pregnancy outcomes, at least partly through PPARγ regulated function of trophoblast.
研究领域:
毒理学
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生殖生物学
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分子生物学
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内分泌学
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产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
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2022
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IF 4.319
Yi Zhang,Xiujin Shi,Jialun Han,Wenxing Peng,Zhenwei Fang,Yang Zhou,Xiaoyu Xu,Jie Lin,Fucheng Xiao,Limin Zhao,Yang Lin
Introduction As the primary immune cells, macrophages play a key role in atherosclerotic progression. M2 macrophage polarization has been reported to promote tissue repair and attenuate plaque formation upon the expression of anti-inflammatory factors. Convallatoxin (CNT) is a natural cardiac glycoside with anti-inflammatory pharmacological properties. However, whether CNT protects against atherosclerosis (AS) and underlying mechanisms is unknown. This work was designed to explore the potential effects of CNT on atherosclerosis.Methods In this study, Apolipoprotein E deficiency (ApoE−/-) mice fed with high-fat diet were established, and CNT (50 or 100 μg/kg) were intragastrically administrated for 12 weeks every day. In vitro, RAW264.7 macrophages stimulated with ox-LDL were treated with CNT (50 or 100 nM) for 24 h. The specific PPARγ antagonist, GW9662, was used to block the PPARγ signaling pathway in vitro. Then, the atherosclerotic lesions, macrophage polarization markers, inflammatory cytokines and PPARγ signaling pathway were examined in further examinations.Results Our results showed that the atherosclerotic lesions were reduced by CNT, as demonstrated by the downregulation of serum lipid level and aortic plaque area in AS mice. Furthermore, we found that CNT treatment promoted the expression of M2 macrophage markers (Arg1, Mrc1, Retnla and Chi3l3), and decreased the levels of pro-inflammatory cytokines (IL-6 and TNF-α), accompanied by the increase of anti-inflammatory factor (IL-10) in aortic vessels of AS mice. In ox-LDL-induced RAW264.7 cells, CNT administration also facilitated macrophages polarizing towards M2 subtype and inhibited inflammatory responses. Furthermore, both the in vivo and in vitro experiments showed CNT could increase the expression of PPARγ, Integrin αv and Integrin β5, and GW9662 could block CNT-induced M2 macrophage polarization.Conclusion Taken together, these data suggest that CNT may promote M2 macrophage polarization to exert an anti-atherosclerotic effect, partially through activating PPARγ-Integrin αvβ5 signaling pathway.
研究领域:
心血管疾病
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免疫学
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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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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2019
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IF 3.845
Linghu Ke-Gang,Wu Guo-Ping,Fu Ling-Yun,Yang Hong,Li Hai-Zhi,Chen Yan,Yu Hua,Tao Ling,Shen Xiang-Chun
1,8-Cineole (eucalyptol), a monoterpene, has been widely reported for the anti-inflammatory effects. Our previous data confirmed that 1,8-cineole ameliorated the inflammatory phenotype of human umbilical vein endothelial cells (HUVECs) by mediating NF-κB expression in vitro. At present, we investigated the protection effects of 1,8-cineole on vascular endothelium in lipopolysaccharide (LPS)-induced acute inflammatory injury mice and the potential mechanisms involved in the protection in HUVECs. Results from enzyme linked immunosorbent assays revealed that 1,8-cineole suppressed the secretion of interleukin (IL)-6 and IL-8 and increased the expression of IL-10 in the serum of LPS-induced mice. 1,8-Cineole reduced the inflammatory infiltration and the expression of vascular cell adhesion molecular 1 (VCAM-1) in the sections of thoracic aorta in LPS-induced acute inflammatory mice. Western blotting indicated that 1,8-cineole significantly decreased the phosphorylation of NF-κB p65 and increased the expression of PPAR-γ in the thoracic aorta tissue. 1,8-Cineole increased the expression of PPAR-γ in LPS-induced HUVECs. 1,8-Cineole and rosiglitazone reduced the protein and mRNA levels of VCAM-1, E-selectin, IL-6, and IL-8 in LPS-induced HUVECs, which could be reversed by the action of GW9662 (inhibitor of PPAR-γ). 1,8-Cineole and rosiglitazone blocked the LPS-induced IκBα degradation and NF-κB p65 nucleus translocation, which could be reversed by the pretreatment of GW9662 or silence of PPAR-γ gene. In conclusion, 1,8-cineole attenuated LPS-induced vascular endothelial cells injury via PPAR-γ dependent modulation of NF-κB.
研究领域:
药理学
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免疫学
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分子生物学
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心血管科学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2018
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IF 3.118
Lina Zhang,Jinghua Gao,Peng Tang,Li Chong,Yue Liu,Peng Liu,Xin Zhang,Li Chen,Chen Hou
Nuciferine, a bioactive component extracted from the lotus leaf , has been reported to have various anti-inflammatory effects. In the present study, we aimed to investigate the anti-inflammatory effects and mechanism of nuciferine on lipopolysaccharide (LPS)-stimulated BV2 microglia cells . The anti-inflammatory activity of nuciferine was measured by ELISA to detect the inflammatory mrdiators secretion in LPS-simulated BV2 microglia cells. The results demonstrated that nuciferine significantly inhibited LPS-induced TNF-α, IL-1β, PGE 2 and NO secretion. LPS-induced NF-κB activation was also suppressed by nuciferine. Further studies showed that nuciferine increased the expression of PPAR-γ. Functional aspects were analyzed using PPAR-γ specific inhibitor GW9662 , which attenuated the LPS-induced secretion of proinflammatory mediators, such as TNF-α, IL-1β, PGE 2 , and NO. In conclusion, these results suggested that nuciferine activated PPAR-γ, which subsequently inhibited LPS-induced inflammation in BV2 cells.
研究领域:
药理学
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免疫学
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神经科学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
MICROCHEMICAL JOURNAL
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2022
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IF 5.304
Qingqing Yao,Jiahuan Chen,Xuechao Li,Wen Yang,Jianan Ning,Qi Liang,Qian Li
The development of site-selective covalent protein immobilization strategies is crucial for many protein-based bioanalytical assays. Herein, we proposed a label-free, site-selective, covalent immobilization strategy for the functionalization of PPARγ on GW9662 modified macroporous silica gels . The gels were characterized by X-ray photoelectron spectroscopy (XPS) and scanning electron microscope (SEM). Molecular docking in combination with competitive study, adsorption energy distribution (AED) calculation, and frontal analysis were used to investigate the binding of ligands with GW9662 occupied PPARγ. Docking results indicated that rosiglitazone , pioglitazone , and gensenoside Rh1 could cooperatively bind to the receptor with GW9662. Competitive studies revealed that the three ligands bond with PPARγ through the same site in the presence of GW9662. AED calculation showed one type of binding site for the three ligands on the receptor. Due to the presence of GW9662, the affinities of the three ligands ((2.35 ± 0.05) × 10 5 M −1 for rosiglitazone, (1.27 ± 0.02) × 10 5 M −1 for pioglitazone, and (3.18 ± 0.13) × 10 5 M −1 for gensenoside Rh1) with PPARγ were one or two orders of magnitude smaller than the literature reported values. The good performance of the immobilized PPARγ provided an opportunity for application in receptor-ligand interactions and cooperative partner screening. Our strategy is, therefore, a promising way to realize the label-free, covalent immobilization of functional proteins.
研究领域:
生物化学
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分析化学
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分子生物学
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蛋白质工程
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色谱学
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产品关联
DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2023
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IF 6.1
Shuhua Shan,Jiaqi Zhou,Ruopeng Yin,Lizhen Zhang,Jiangying Shi,Qinqin Qiao,Zhuoyu Li
Non-alcoholic fatty liver disease (NAFLD) is a serious health problem worldwide. Impeding fatty acid uptake may be an attractive therapeutic strategy for NAFLD. In the current study, we found that millet bran protein hydrolysate (MBPH) prepared by in vitro gastrointestinal bionic digestion exhibits the potential of anti-NAFLD in vitro and in vivo, characterized by the alleviation of hepatic steatosis and the reduction of lipid accumulation. Further, MBPH significantly decreased the expression levels of fatty acid uptake related genes (FABP1, FABP2, FABP4, CD36, and CPT-1α) of liver tissue in a NAFLD mice model through activating peroxisome proliferator-activated receptor γ (PPARγ) and efficiently restrained the fatty acid uptake of liver tissue, thus exerting anti-NAFLD activity. As expected, the anti-NAFLD effect induced by MBPH, characterized by the alleviation of hepatic vacuolar degeneration, hepatic steatosis, and fibrosis, was effectively abrogated with PPARγ inhibitor (GW9662) treatment. These results indicate that the retardant of fatty acid uptake induced by PPARγ activation may be the critical factor for the anti-NAFLD effect of MBPH. Collectively, MBPH has the potential as a next-generation dietary supplementation for the prevention and treatment of NAFLD.
研究领域:
营养学
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药理学
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肝病学
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分子生物学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
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IF 6.1
Hongyi Xian,Ruobing Bai,Yu Feng,Shiyue Tang,Zhiming Li,Chudan Gao,Kaiwei Li,Boxuan Liang,Yizhou Zhong,Yuji Huang,Hao Li,Yanhong Deng,Xiaohong Yang,Xiyun Huang,Xiaoqing Chen,Xingfen Yang,Zhenlie Huang
Polylactic acid (PLA), a biodegradable plastic, is increasingly promoted as a sustainable alternative to conventional plastics. However, its degradation under non-composting conditions and associated toxicological impacts remain insufficiently understood. This study aimed to compare the toxicity of PLA microplastics (MPs) at different degradation stages, including PLA polymers, oligomers, and aged polymers, in zebrafish larvae. Zebrafish were exposed to environmentally relevant concentrations (0.1, 1, and 10 mg/L), and morphological, biochemical, and transcriptomic analyses were performed. PLA MPs disrupted lipid metabolism, decreased ATP levels, and elevated reactive oxygen species production, ultimately leading to cardiac malformations. Mechanistically, PLA MPs activated the peroxisome proliferator-activated receptor γ (PPARγ), upregulating genes related to lipid storage and cardiac development. Co-exposure with a PPARγ antagonist GW9662 partially alleviated these effects, confirming the role of PPARγ-mediated pathways in PLA MP-induced lipid disruption and cardiotoxicity. Notably, PLA polymers showing stronger cardiac dysfunction than PLA oligomers and ultraviolet (UV)-aged PLA polymers. These findings provided critical evidence that PLA MPs impair energy homeostasis and cardiac development in zebrafish, underscoring the urgent need for comprehensive ecological risk assessments of PLA-based materials under realistic environmental conditions.
研究领域:
环境毒理学
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海洋污染
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生态毒理学
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发育生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Environmental Chemistry and Ecotoxicology
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2025
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IF 8.2
Jinzhi Ren,Ying Peng,Chenyang Sun,Yining Zhang,Jianjun Li,Simin Xia,Caixia Gao,Yimeng Wang,Xiangping Nie
There is an urgent need for a more efficient and ethical approach to chemical toxicity assessment. The emergence of New Approach Methodologies (NAMs) based on fish embryos transcriptomics provides a promising alternative. Triphenyl phosphate (TPP) — a pervasive contaminant in estuaries — disrupts lipid homeostasis in mammals via PPARγ activation, yet its ecotoxicological impacts on estuarine fish remain unknown. Leveraging NAMs, this study integrates concentration-dependent transcriptomics (CDT), molecular docking, and phenotypic toxicity assays to unravel effects of TPP on embryonic development and lipid metabolism in the benthic fish Mugilogobius chulae . We found that TPP induced significant lethality (LC₅₀ = 1.86 × 10 6 ng/L) and teratogenicity (EC₅₀ = 5.27 × 10 5 ng/L), suppressing spontaneous movement, heart rate, and hatching. At concentrations of 5270 ng/L and 52,700 ng/L, TPP elevated triglycerides, total cholesterol, and hepatotoxicity markers (alanine aminotransferase / aspartate aminotransferase). CDT analysis identified fatty acid metabolism pathways as the most sensitive targets, with TPP upregulating PPARγ while downregulating CD36 and ACSL5 — indicating blocked fatty acid oxidation and explaining lipid accumulation. Crucially, co-exposure with PPARγ antagonist GW9662 reversed metabolic disorders, validating the mechanistic role of PPARγ. Furthermore, molecular docking confirmed that TPP binds PPARγ with agonist-like affinity. This work establishes a NAM-based framework for deciphering the toxicity of contaminants of emerging concern in estuarine ecosystems, offering novel tools for ecological risk assessment.
研究领域:
生态毒理学
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环境科学
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毒理基因组学
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分子生物学
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水生毒理学
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产品关联
DOI
高影响因子
FASEB JOURNAL
·
2025
·Vol. 39
·期 22
·e71232
·
IF 4.2
Yinye Yao,Chunjing Xu,Yongfu Shao,Xiaoqing Xu,Qian Yin,Xinyuan Cao,Meifang Zheng,Duqin Zhao,Wangye Zheng,Jiaojiao Ni,Jieer Ying,Yunben Yang
Biliary tract cancer (BTC) remains highly challenging owing to its poor prognosis. Although gemcitabine plus cisplatin (Gem/Cis) represents a standard chemotherapy option, treatment resistance significantly limits the outcomes. Metabolic reprogramming influences therapeutic response; however, the specific metabolic determinants of chemosensitivity in BTC are poorly defined. Using untargeted metabolomics followed by targeted validation, we found that plasma linoleic acid (LA) levels were significantly elevated in patients with chemotherapy-responsive BTC. LA supplementation led to tumor accumulation and synergistically enhanced Gem/Cis-induced cytotoxicity in vitro and in vivo. Mechanistic investigations revealed that LA activated retinoic acid receptor gamma (RARγ), and pharmacological or genetic ablation of RARγ abolished the chemosensitizing effects of LA, establishing RARγ as an important mediator. Activation of the LA-RARγ axis orchestrated a dual proapoptotic and pro-immune transcriptional program. This resulted in increased cancer cell apoptosis and a remodeled immune microenvironment, characterized by reduced PD-L1 expression and enhanced CD8 + T cell activation. Taken together, this study identified LA as a novel metabolic modulator that potentiates chemotherapy response in BTC through RARγ activation, orchestrating a dual antitumor response by promoting cancer cell apoptosis and enhancing antitumor immunity. Graphical Linoleic acid (LA) potentiates chemotherapy response in biliary tract cancer (BTC) by activating the nuclear receptor RARγ. In addition to inhibiting cell proliferation, the LA-RARγ axis drives a powerful dual response: promoting cancer cell apoptosis and enhancing antitumor immunity (Created with BioRender.com).
研究领域:
肿瘤学
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癌症代谢
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分子生物学
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免疫治疗
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药理学
✓ 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）