ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
·
IF 6.6
Fuhui Yan,Liwen Peng,Xiao Han,Xingxing Han,Miaoliang Wu,Zhi Bai,Xiaoshan Liu
Triphenyl phosphate (TPhP) is a commonly used organophosphorus flame retardant, and its potential health risks to mothers and infants are considerable. Our previous research revealed that gestational TPhP exposure significantly reduces the depth of placental implantation and impairs uterine spiral arteries remodelling, leading to preeclampsia (PE)-like symptoms, but the underlying mechanism remains unclear. In this study, we further demonstrate that TPhP activated the transcription of Phosphatase and tensin homolog (PTEN) by activating peroxisome proliferator activated receptor gamma (PPARγ). This activation subsequently inhibits the PI3K-AKT-mTOR signaling pathway, modulates autophagy homeostasis, and inhibits the migration and invasion of extravillous trophoblast (EVT) cells. Notably, knockdown of PTEN or PPARγ with shRNA, or inhibition of autophagy with chloroquine (CQ) alleviates the TPhP-induced inhibition of EVT cells migration or invasion. Furthermore, using an established murine intrauterine exposure model, we confirmed that TPhP activates PPARγ, increases PTEN expression in placental trophoblast, inhibits the PI3K-AKT-mTOR signaling pathway and disturbs autophagy homeostasis. Collectively, these findings elucidate that TPhP inhibits EVT cells migration and invasion via the PPARγ-PTEN-PI3K-AKT-mTOR mediated autophagy pathway, providing a new toxicity pathway in placental toxicology. Additionally, this study provides new insights into the etiological research of PE.
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高影响因子
Food Frontiers
·
2025
·
IF 6.9
Jie Li,Qihui Zhu,Yang Li,Haiyu Zhao,Yi Bi,Chuanying Pan,Min Wang,Lin Han,Xianyong Lan
Phloretin, a plant-derived dihydrochalcone bioactive compound, potentially modulates preadipocyte differentiation, although this remains controversial and requires further clarification. To clarify this point, herein, phloretin gavage inhibited mice obesity, reduced adipocyte size, and ameliorated serum lipid parameters, including triglycerides. In vitro, phloretin suppressed the differentiation of 3T3-L1 and bovine preadipocytes, decreasing lipid droplet content and reducing CEBPα and PPARγ levels. Moreover, during differentiation, glutathione peroxidase (GSH-Px) ultimately decreased with elevations in malondialdehyde (MDA) and Fe 2+ levels, along with acyl-CoA synthetase long-chain family member 4 ( ACSL4 ), P53 , and SLC7A11 expression, indicating differentiation occurring under mild oxidation and slight ferroptosis activation. Similar to (1 S ,3 R )-RSL3, phloretin further stimulated the ferroptosis pathway by inhibiting glutathione reductase (GR) and GSH-Px, increasing the content of MDA and Fe 2+ . Simultaneously, the suppression of Fth1 , Slc7a11 , and Sod2 transcription, significantly elevated HMGB1 protein, and markedly downregulated glutathione peroxidase 4 (GPX4) and TFR protein collectively confirmed that phloretin activated the ferroptosis signaling pathway to inhibit differentiation. Further phosphoproteomic analysis identified dm-phosphorylation sites (p-eEF2K[S365], p-AMPKα1[S491], and p-CaMKK2[S495]) enriched in AMPK/MAPK signaling pathways and transferrin receptor binding. Further molecular docking simulations revealed that phloretin binds to PPARγ or transferrin to activate ferroptosis pathway, revealing the potential crosstalk between ferroptosis signaling pathway and adipogenic differentiation processes.
研究领域:
分子生物学
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细胞生物学
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脂肪生成
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营养生物化学
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药理学
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氧化应激与细胞死亡
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高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2025
·
IF 11.3
Pu Chen,Ziyuan Li,Gan Miao,Xiaopeng Tang,Chengying Zhou,Li Zhao,Xiaoting Jin,Guangbo Qu,Yuxin Zheng,Guibin Jiang
Organophosphate esters (OPEs) have emerged as a significant environmental concern due to their widespread occurrence and potential human health risks. The presence of OPEs in human blood suggests direct interactions with hematological components, which may compromise hemostatic balance and lead to adverse health outcomes. Despite the critical role of hemostatic balance in maintaining blood stability, the effects of OPEs on this system remain poorly understood. This investigation was undertaken to delineate the effects and potential mechanisms of OPEs that modulate hemostasis, utilizing in silico approach and high-throughput in vitro investigation. We analyzed 85 environmentally prevalent OPEs for their structural descriptors and affinity for proteins essential to hemostatic function. The multiple linear regression implicated aryl-OPEs, distinguished by their benzene ring scaffold, as potent disruptors of hemostatic balance. This analysis result was rigorously validated through the in vitro hemostatic balance assays. Further investigation through network toxicology, artificial intelligence (α-Fold) algorithms, and an agonist cotreatment assay revealed proliferator-activated receptor γ (PPARγ) as a key mediator of aryl-OPEs induced hemostatic disruption. By integrating in vitro experimental insights with in vivo exposure data, we concluded that specific aryl-OPEs, such as bisphenol a bis (diphenyl phosphate) (BDP) and cresyl diphenyl phosphate (CDP), pose a moderate risk to the hemostatic balance of the general population. Our findings not only contribute to the prioritization of OPEs risk management but also establish a methodology for assessing the hematological toxicity of emerging pollutants.
研究领域:
环境科学
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毒理学
·
生物信息学
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PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Xuan Liu,Xijuan Ren,Zhonghua Fan,Penghui Mao,Mingqing Qian,Tingting Qian,Ying Yang,Hui Liu,Li Wang
Triphenyltin (TPT), a widely utilized organotin compound, serves marine, agricultural, and industrial applications. TPT is commonly found in estuaries and coastal regions. However, recent studies on environmental pollution have identified TPT as a pollutant due to its pronounced pollutant characteristics and potential implications for human health. Research from the past has demonstrated that TPT can cause issues with lipid metabolism. However, the specific metabolites affected and the involvement of the PPAR pathway remain unknown. Herein, male Sprague-Dawley (SD) rats received oral administration of TPT at daily doses of 0.5, 1, and 2 mg/kg for a period of 28 days. To investigate the abnormal metabolism in TPT-exposed rats, liver samples were analyzed using LC-MS/MS non-targeted metabolomics. Validated in vitro experiments were also performed using BRL-3A cells. This study suggests that exposure to TPT causes liver injury, increases lipid accumulation, and alters PPARγ expression levels. The findings highlight the need for restrictions on its use and further investigation of its toxic effects on other organs and systems to better assess its potential impact on human health.
研究领域:
毒理学
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环境科学
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代谢组学
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分子生物学
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内分泌学
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PubMed
高影响因子
MOLECULAR GENETICS AND GENOMICS
·
2025
·Vol. 300
·期 1
·1-16
·
IF 2.1
Tian Xinyuan,Bai Xiaoping,Han Yunqi,Ye Yu,Peng Meiling,Cui Hongwei,Li Kai
PPAR γ, as a widely present receptor in tissues, plays a key role in lipid metabolism, energy balance, inflammatory response, and cell differentiation. It plays an important role in the occurrence and development of various tumors, including prostate cancer, gastric cancer, lung cancer, etc., by regulating lipid metabolism. However, the specific mechanism by which it affects lung cancer growth is not yet clear. To investigate how PPAR γ affects lung cancer cell growth by altering ALDH1A3 levels through its impact on lipid metabolism. Bioinformatics analysis was used to predict the correlation between PPAR γ, ALDH1A3 and lung cancer. Based on the results of bioinformatics analysis, PPAR γ activator (Pioglitazone, Pio) and ALDH1A3 inhibitor (diethylaminobenzaldehyde, DEAB) were used to act on lung cancer cells and observe their growth. After measuring the IC50 value of the drug in vitro experiments, lipid metabolomics analysis was conducted to identify the significant changes in differential metabolites and metabolic pathways under the combined influence of Pio and DEAB. Through bioinformatics analysis, it was found that there were significant differences in the levels of PPAR γ and ALDH1A3 between lung cancer and normal lung tissues, and ALDH1A3 was positively correlated with PPAR γ. AUC analysis found that PPAR γ and ALDH1A3 have good predictive value in the diagnosis and prognosis of lung cancer. GSEA enrichment analysis showed that PPAR γ and ALDH1A3 were significantly correlated with lipid oxidation. Combining relevant literature to demonstrate the inhibitory effect of PPAR γ receptors on lung cancer cells and the ability of PPAR γ activation to inhibit ALDH1A3 levels. Further in vitro CCK-8 and IC50 measurements of lung cancer cells A549 and H1299 were conducted, followed by non targeted lipidomics analysis. It was found that the metabolic pathways upregulated by activation of PPAR γ and inhibition of ALDH1A3 included glycerophospholipid metabolism, cholesterol metabolism, arachidonic acid metabolism, and fat digestion and absorption, with glycerophospholipid metabolism pathway accounting for the highest percentage. Conclusion: PPAR γ activation can inhibit the production of ALDH1A3, alter the glycerophospholipid metabolism pathway, and thus inhibit the proliferation of lung cancer cells. This study confirms that PPAR γ affects lung cancer proliferation by influencing the glycerophospholipid metabolism pathway.
研究领域:
肿瘤学
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分子生物学
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代谢学
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药理学
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PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2018
·Vol. 447
·期 1
·137-149
·
IF 2.561
Wu Weiche,Wang Sisi,Xu Ziye,Wang Xinxia,Feng Jie,Shan Tizhong,Wang Yizhen
Betaine, a neutral zwitterionic compound, could regulate intramuscular fat (IMF) deposition and meat quality. However, the efficacy is controversial. Moreover, the regulatory mechanism of betaine on lipid metabolism in skeletal muscle cells remains unclear. Therefore, in this study, we examined the effects and regulatory mechanism of betaine on lipid accumulation in adipogenic-differentiated C2C12 cells. We found that adipogenic-induced C2C12 cells treated with 10 mM betaine for 24 and 48 h had more lipid accumulation than the control group. Real-time PCR and Western blot results revealed that betaine treatment did not alter the expression of lipolysis and lipid oxidation-related genes, but dramatically increased the expression of peroxisome proliferator-activated receptor γ (PPARγ) and its target genes such as fatty acid binding protein 4 (aP2), fatty acid synthase (FAS) and lipoprteinlipase (LPL). Furthermore, betaine combined with PPARγ inhibitor GW9662 treatment showed that betaine elevated C2C12 lipid accumulation through upregulation of PPARγ. Mechanistically, we found that betaine promoted PPARγ expression and lipid accumulation through inhibition of extracellular regulated protein kinases1/2 (ERK1/2) signalling pathway. These results demonstrate that betaine acts through ERK1/2-PPARγ signalling pathway to regulate lipid metabolism in adipogenic-differentiated skeletal muscle cells, which could provide some useful information for controlling muscle lipid accumulation by manipulating ERK1/2 and PPARγ signalling pathway.
研究领域:
生物化学
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细胞生物学
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分子生物学
·
营养学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Cheng Fu,Tianyi Hu,Xiangli Zhao,Yahui Huang,Jiang zhang,Lan Zhu,Jun Yang,Gang Chen
Rhein, an anthraquinone-derivative monomer isolated from the rhubarb plant, is the active ingredient of the drug Diacerein® (generic name: diacetylrhein), which possesses anti-inflammatory and antioxidant properties. It has been reported that rhein is effective in protecting against cerebral and retinal ischemia–reperfusion injury (IRI), but whether it can protect against renal IRI remains unknown. Here, a lethal renal IRI model was established with a 100 % mortality rate in untreated mice. Treatment with 100 mg/kg of rhein for 5 consecutive days before ischemia resulted in 100 % survival, maximal preservation of renal function, and a significant reduction in pathological damage, apoptosis and inflammation. In addition, rhein pretreatment significantly inhibited the upregulation of NLRP3, caspase-1, IL-1β and NGAL seen in the IRI control group. Through a series of experiments (including Co-Immunoprecipitation (Co-IP), pull-down, molecular dynamics simulation and surface plasmon resonance (SPR)), we confirmed that rhein has a strong binding affinity with PPARγ. By using the specific inhibitor T0070907 to block PPARγ, the protective effect of rhein on renal IRI in vivo and the protective effect on cell damage in the NLRP3 inflammasome activation model induced by (LPS + Nig) in vitro can be largely eliminated. We demonstrate here that rhein can potently protect against lethal renal IRI in mice. This protection is mainly achieved by targeting and enhancing the expression of PPARγ, thereby inhibiting the activation of the NLRP3 inflammasome. Thus, rhein may be therapeutically useful for the clinical prevention and treatment of renal IRI.
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ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2026
·
IF 12.2
Zhendong Yang,Tingyu Li,Wenyuan Su,Wangjing Zhai,Zhengzhe Wan,Yong Liang,Ting Ruan,Guibin Jiang
The activation of peroxisome proliferator-activated receptor γ (PPARγ) represents a primary biological mechanism underlying the adverse effects of environmental adipogens. However, a holistic understanding of the composition profiles of PPARγ agonists in complex environmental matrices remains elusive. In this study, an integrated workflow of knowledge-based suspect screening combined with in vitro bioassays enabled the comprehensive identification and prioritization of the main contributing components in indoor dust from Chinese residential areas. All mixed dust extracts activated PPARγ within the exposure concentration range (7.8 × 10–2–10 mg dust/mL assay medium). A total of 123 putative agonists covering 35 structural categories were found, among which 30 chemicals were verified as specific PPARγ agonists through reference standards and in vitro assays. These agonists could explain up to 84% of the effect in the mixed dust extracts, with phthalates (31% ± 19%), fatty acids (12% ± 9%), quaternary ammonium compounds (2% ± 1%), and hydrocarbon surfactants (2% ± 1%) being the major contributors. The concentration addition model was validated to effectively characterize the combined effects of these PPARγ agonists via the artificial mixture experiments. These results suggest that the workflow holds promise for the overall perception of bioactive components related to toxicological end points in environmental samples.
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Chang Liu,Zhuoqun Wang,Linxin Zhang,Di Yang,Zhihong Zhang,Xiaoli Cui,Ali H. Eid,Mengyang Wang
Background and Purpose Fangchinoline (FAN), a bioactive bisbenzylisoquinoline alkaloid from Stephania tetrandra , shows protective potential against angiotensin II (Ang II)-induced hypertensive heart failure (HF), particularly involving mitophagy and ferroptosis, remain unclear. We investigated the effects of FAN on Ang II-induced cardiac remodelling and HF. Experimental Approach A hypertensive heart failure model was established in C57BL/6 mice via 4-week Ang II infusion. FAN was administered during the final 2 weeks. Cardiac function was assessed by echocardiography and pathological remodelling was evaluated by histological staining. RNA sequencing of cardiac tissue was performed to investigate the mechanism of anti-heart failure action of FAN. The potential binding proteins of FAN were verified by molecular docking, drug affinity response target stability (DARTS), cellular thermal shift assay (CETSA) and surface plasmon resonance assay (SPR). In vitro , neonatal rat ventricular myocytes (NRVMs) were used to investigate the effects of FAN on cellular hypertrophy, mitophagy and ferroptosis. Key Results In vivo , FAN treatment significantly ameliorated cardiac hypertrophy, dysfunction and fibrosis. These protective effects were independent of blood pressure-lowering actions. Mechanistically, FAN activates PGC-1α to enhance mitophagy and suppress STAT6-PPARγ signalling, thereby inhibiting ferroptosis and restoring redox homeostasis. In vitro , FAN reduced Ang II-induced NRVM hypertrophy, ROS production and mitochondrial membrane potential depolarisation, and confirmed the modulation of mitophagy and ferroptosis markers. Conclusions and Implications We demonstrate that FAN alleviates Ang II-induced HF through a mechanism involving the activation of PGC-1α-mediated mitophagy and regulation of the STAT6-PPARγ pathway, ultimately suppressing cardiomyocyte ferroptosis. These results offer new perspectives for HF treatment. Graphical FAN mitigates HF by engaging PGC-1α-mediated mitophagy and STAT6-PPARγ to counteract ferroptosis.
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PubMed
高影响因子
Antioxidants
·
2026
·Vol. 15
·期 6
·676
·
IF 8.2
Ze-Yun Cao,Xun Zou,Hong-Li Li,Xuan Kong,Li-Long Pan,Jun Yang,Xiao-Liang Dong
Hypertriglyceridemic acute pancreatitis (HTG-AP) progresses rapidly with poor prognosis. Intestinal barrier dysfunction and excessive oxidative stress contribute to its pathogenesis, but specific mediators linking gut injury, oxidative stress and pancreatic damage remain unclear. Here, we identify endogenous phenyllactic acid (PLA) as a critical metabolite regulating intestinal barrier integrity and oxidative homeostasis in HTG-AP. We noted serum PLA, a disease-associated metabolite whose reduction correlates with gut dysbiosis and pancreatic inflammation in HTG-AP. PLA supplementation in HTG-AP mice attenuated intestinal barrier dysfunction and mitigated intestinal oxidative stress, as evidenced by improved gut dysbiosis, reduced reactive oxygen species accumulation, restored superoxide dismutase activity, restored barrier integrity, reduced bacterial translocation to the pancreas, and decreased serum lipopolysaccharide levels, ultimately mitigating pancreatic injury. RNA sequencing of colonic tissue revealed peroxisome proliferator-activated receptor (PPAR) signaling as one of the most significantly altered pathways in HTG-AP. PPARγ expression was markedly reduced in colonic epithelial cells and upregulated upon PLA treatment. Knockdown of colonic epithelial PPARγ via adeno-associated virus abrogated the beneficial effects of PLA on intestinal barrier integrity, oxidative stress and pancreatic injury in HTG-AP mice. The protective effects of PLA were phenocopied by the PPARγ agonist rosiglitazone. Collectively, these findings identified gut microbiota-derived PLA as an endogenously derived metabolite modulating intestinal oxidative stress and barrier function. Using male C57BL/6J mice to establish an HTG-AP model, we further revealed that PLA exerts protective effects against HTG-AP by targeting colonic PPARγ to modulate the gut–pancreas axis, highlighting PLA as a promising candidate for targeted intervention in HTG-AP.
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高影响因子
JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
·
2026
·
IF 1.6
Yan Wu,Juan Du,Xiao-Lei Zhang
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor dysfunction and neuroinflammation. This study investigated the neuroprotective effects of ginsenoside Rg1 in an MPTP-induced PD mouse model. Behavioral tests showed that Rg1 significantly improved motor coordination and emotional behavior. Rg1 also stabilized monoamine neurotransmitter levels in the cortex, striatum, and substantia nigra, and reduced the expression of inflammatory cytokines. Histological and molecular analyses further demonstrated that Rg1 alleviated nigrostriatal injury. Mechanistically, Rg1 increased PPARγ expression and inhibited MAPK signaling activation. These findings suggest that Rg1 ameliorates PD-like pathology through modulation of neuroinflammation and neurotransmitter homeostasis.
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PubMed
高影响因子
CELL BIOLOGY AND TOXICOLOGY
·
2026
·
IF 5.7
Zhao Bingbing,Zhang Zhengwei,Li Xiaoxue,Dong Shiyun,Zhong Xin,Li Zhitao,Jin Ye,Bai Yun,Wei Can
Liver fibrosis represents a major unmet clinical challenge, and induction of hepatic stellate cell (HSCs) senescence has emerged as a promising therapeutic strategy to halt or reverse fibrotic progression. PPARγ is a key regulator of HSCs quiescence; however, the downstream molecular mechanisms mediating its pro-senescence effects remain poorly defined. Here, we demonstrate that PPARγ expression is markedly reduced in a CCl₄-induced mouse liver fibrosis model and that its restoration drives HSC inactivation and senescence. Through integrated bioinformatics analysis and functional validation in PPARγ-overexpressing HSC-T6 cells, we identified leukemia inhibitory factor receptor (LIFR) as a direct transcriptional target of PPARγ. Mechanistically, PPARγ upregulates LIFR to suppress STAT3 phosphorylation, thereby downregulating fibrosis markers CO Ⅰ and α-SMA, elevating P21 and γ-H2A.X, and reducing CCND1. Crucially, LIFR knockdown abolished all PPARγ-mediated effects, confirming its indispensable role in this axis. Furthermore, combined treatment with the STAT3 inhibitor WP1066 synergistically enhanced PPARγ-driven HSC senescence in a LIFR-dependent manner. These findings establish a PPARγ-LIFR-STAT3 signaling cascade as a critical regulator of HSCs fate, and suggest that pharmacological activation of this axis represents a tractable approach for fibrosis resolution.
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