BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Xinxin Lin,Xiaocong Liu,Jinglin shi,Tuohong Sun,Ting Feng,Benrui Sun,Hongbin Liang,Qiuxia Zhang,Guojun Chen,Siyu Chen,Alex Pui-Wai Lee,Shenjian Luo,Jiancheng Xiu,Xinlu Zhang
Arterial remodeling is strongly linked to cardiovascular morbidity and mortality. Adventitial inflammation is a key driver in the pathological process of arterial remodeling. However, the underlying molecular mechanism remains largely unknown. This study was conducted to elucidate the role and mechanism of peroxisome proliferator-activated receptor alpha (PPARα) in arterial remodeling. Here, by using the transverse aortic constriction (TAC) model to mimic overload pressure-induced arterial remodeling, we observed significantly decreased expression of PPARα in macrophages that infiltrated into the remodeled arterial adventitia, whereas the administration of PPARα agonist Wy14643 efficiently ameliorated such arterial changes, especially in adventitia. PPARα activation strengthened its interaction with yes-associated protein (YAP) in the cytoplasm thus decreasing the translocation of YAP into nucleus to trigger macrophage infiltration and polarization toward the classical activation phenotype. Finally, blockade of YAP signaling could also suppress pathological arterial alternations in the TAC model. Our study thus identifies PPARα as a promising therapeutic target for treating arterial remodeling.
研究领域:
心血管病学
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分子生物学
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免疫学
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信号转导
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转化医学
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2022
·
IF 5.195
Manyun Dai,Wan Peng,Ting Zhang,Qi Zhao,Xiaofang Ma,Yan Cheng,Chunyan Wang,Fei Li
Ethnopharmacological relevance Tripterygium glycosides tablets (TGT) and Tripterygium wilfordii tablets (TWT) have been used to treat autoimmune diseases clinically, however, the side effects of TWT are higher than TGT, especially for hepatotoxicity. The aim of the study This study aims to determine the mechanism of TWT-induced liver injury. Materials and methods We performed metabolomic analysis of samples from mice with liver injury induced by TGT and TWT. Ppara -null mice were used to determine the role of PPARα in TWT-induced liver injury. Results The results indicated that TWT induced the accumulation of medium- and long-chain carnitines metabolism, which was associated with the disruption of PPARα-IL6-STAT3 axis. PPARα agonists fenofibrate could reverse the liver injury from TWT and TP/Cel, and its protective role could be attenuated in Ppara -null mice. The toxicity difference of TWT and TGT was due to the different ratio of triptolide (TP) and celastrol (Cel) in the tablet in which TP/Cel was lower in TWT than TGT. The hepatotoxicity induced by TP and Cel also inhibited PPARα and upregulated IL6-STAT3 axis, which could be alleviated following by PPARα activation. Conclusions These results indicated that PPARα plays an important role in the hepatotoxicity of Tripterygium wilfordii , and PPARα activation may offer a promising approach to prevent hepatotoxicity induced by the preparations of Tripterygium wilfordii .
研究领域:
药理学
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毒理学
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代谢组学
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分子生物学
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DOI
PubMed
高影响因子
Journal of Advanced Research
·
2026
·
IF 17.1
Hangjun Zhang,Hongmei Yang,Yongjian Shao,Xindi Ye,Xuetong Qu,Zhiquan Liu
Introduction Antibiotics are frequently detected in aquatic environments, and previous studies have explored antibiotic effects on aquatic organisms. However, the molecular mechanism linking sulfamethoxazole (SMX) and lipid metabolism in amphibians remains unclear. Objectives To assess the ecotoxicological mechanisms and environmental risk of SMX pollution. Methods Here, the effect of SMX on lipid metabolism was assessed in P. nigromaculata by screening typical symptoms, including substance contents, enzyme activities, and gene expression in lipid digestion, lipid synthesis, and lipid transport metabolism. This assessment was subsequently validated through molecular docking (MD), molecular dynamics simulation (MDS), and in vitro spectroscopic analysis. Additionally, to evaluate the role of peroxisome proliferator-activated receptors α (PPARα), frogs were exposure to 1 μM of PPARα antagonist GW6471 alone and in conjunction with concentrations of 10 μg/L SMX, over a duration of 21 days. Results SMX at environmentally relevant concentrations induced lipid metabolism disorder, evidenced by an increase in the hepatosomatic index and the accumulation of triglycerides and total cholesterol. Transcriptomic data identified PPARα as primary molecular targets, with both concentrations of SMX perturbing fatty acid metabolism and gene set enrichment analysis revealing enrichment in PPAR pathway. Subsequently, MD, MDS, and in vitro spectroscopic spectra further confirmed that SMX may bind directly to frog PPARα. To further assess the role of PPARα, the frog was exposed to SMX, a PPARα agonist (WY-14643) or co-exposed to SMX with a PPARα antagonist (GW6471) for 21 days. Antagonist co-exposures counteracted the increased lipid content altered by SMX, indicating that PPARα plays a key role in SMX-induced lipid metabolic disorder. Conclusion Our study revealed that exposure to SMX at environmentally relevant concentrations led to lipid metabolic disorder in frogs via PPARα, providing new insights into the potential hazards of antibiotics at environmentally relevant concentrations.
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高影响因子
Theranostics
·
2020
·
IF 8.579
Yaru Li,Mingming Chen,Yu Zhou,Chuanfeng Tang,Wen Zhang,Ying Zhong,Yadong Chen,Hong Zhou,Liang Sheng
Background: Inflammation and steatosis are the main pathological features of alcoholic liver disease (ALD), in which, inflammation is one of the critical drivers for the initiation and development of alcoholic steatosis. NIK, an inflammatory pathway component activated by inflammatory cytokines, was suspected to link inflammation to hepatic steatosis during ALD. However, the underlying pathogenesis is not well-elucidated. Methods: Alcoholic steatosis was induced in mice by chronic-plus-binge ethanol feeding. Both the loss- and gain-of-function experiments by the hepatocyte-specific deletion, pharmacological inhibition and adenoviral transfection of NIK were utilized to elucidate the role of NIK in alcoholic steatosis. Rate of fatty acid oxidation was assessed in vivo and in vitro . PPARα agonists or antagonists of MEK1/2 and ERK1/2 were used to identify the NIK-induced regulation of PPARα, MEK1/2, and ERK1/2. The potential interactions between NIK, MEK1/2, ERK1/2 and PPARα and the phosphorylation of PPARα were clarified by immunoprecipitation, immunoblotting and far-western blotting analysis. Results: Hepatocyte-specific deletion of NIK protected mice from alcoholic steatosis by sustaining hepatic fatty acid oxidation. Moreover, overexpression of NIK contributed to hepatic lipid accumulation with disrupted fatty acid oxidation. The pathological effect of NIK in ALD may be attributed to the suppression of PPARα, the main controller of fatty acid oxidation in the liver, because PPARα agonists reversed NIK-mediated hepatic steatosis and malfunction of fatty acid oxidation. Mechanistically, NIK recruited MEK1/2 and ERK1/2 to form a complex that catalyzed the inhibitory phosphorylation of PPARα. Importantly, pharmacological intervention against NIK significantly attenuated alcoholic steatosis in ethanol-fed mice. Conclusions: NIK targeting PPARα via MEK1/2 and ERK1/2 disrupts hepatic fatty acid oxidation and exhibits high value in ALD therapy.
研究领域:
肝病学
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分子生物学
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病理学
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PubMed
高影响因子
Toxics
·
2026
·Vol. 14
·期 3
·234
·
IF 4.9
Yuyao Jiang,Zijie Ding,Ruolin Hu,Jason T. Magnuson,Shiyan Li,Dingnan Wang,Shengli Zhou,Yirong Guo,Yang Wang,Yuanyuan Liu,Shuying Li,Wenjun Gui
With the global population predicted to reach 10 billion by 2050, pesticides are essential for agricultural production. However, they can introduce chemical stressors into aquatic ecosystems. Chlorpyrifos (CPF) is a widely used organophosphate insecticide that can enter aquatic environments and poses potential risks to early-life-stage fish. Because the retina is an extension of the central nervous system and vision-guided behaviors are highly sensitive to neural dysfunction, we hypothesized that CPF exposure disrupts neurobehavioral and visual function via oxidative stress and PPARα-related signaling. Zebrafish larvae were exposed to CPF (0.01, 0.1, 1, 10, and 100 μg/L) with a vehicle control (VC). During the photomotor response assay, exposure to 100 μg/L CPF reduced overall swimming activity by 48.90% and dark-period activity by 57.71%, whereas 1 μg/L CPF modestly increased total distance by 6.96% (p= 0.003) and dark-period distance by 5.40% (p= 0.011). Transcriptomic profiling highlighted nervous- and vision-related functional categories, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment implicated pathways including gonadotropin-releasing hormone (GnRH), mitogen-activated protein kinase (MAPK), and peroxisome proliferator-activated receptor (PPAR) signaling. Targeted neurotransmitter metabolomics showed significant increases in dopamine, γ-aminobutyric acid (GABA), and acetylcholine across treatment groups, indicating broad neurotransmitter dysregulation. Consistent with these findings, neuronal fluorescence inTg(elavl3: EGFP) larvae decreased by 12.1% and 32.5% in the 1 and 100 μg/L groups, respectively (p< 0.001), and glial fibrillary acidic protein (GFAP) immunofluorescence increased in the eye/brain/olfactory bulb at 1 μg/L (p= 0.037) and 100 μg/L (p= 0.002). Histology further showed retinal injury, with a 14.3% reduction in photoreceptor layer thickness at 100 μg/L (p= 0.034). Mechanistically, coexposure to a PPARα antagonist (GW6471) alleviated CPF-induced behavioral deficits (1.80-fold increase in dark locomotion) and reduced elevated GABA and dopamine levels by 36.8% and 47.3%, respectively. Together, these results indicate that CPF can impair neuro-visual development and that oxidative stress and PPARα-related signaling are closely associated with these effects.
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PubMed
高影响因子
MOLECULES
·
2018
·Vol. 23
·期 7
·1654
·
IF 3.098
Xiaozhi Qiao,Yunlan Li,Jiaqi Mai,Xiaoqing Ji,Qingshan Li
Dibutyltin dilaurate (DBTD) has multiple applications in daily life. However, DBTD is easily deposited in the liver and affects liver functions. This study was designed to explore the effects of DBTD on triglyceride metabolism in human normal hepatocyte HL7702 cells. Our results showed that the intracellular fat contents were dose-dependently decreased by DBTD. The expression of lipolysis genes and proteins were elevated while the lipogenesis genes and proteins were diminished by DBTD. The phosphorylation levels of ribosomal S6 kinase 1 were reduced by both rapamycin and DBTD, indicating that the mTOR pathway was suppressed possibly. The decreased sterol regulatory element-binding protein 1C (SREBP1C) transcription levels, as well as the increased peroxisome proliferator-activated receptor alpha (PPARα) transcription levels, caused by rapamycin and DBTD corresponded to the inactive mTOR pathway. In conclusion, it was possible that DBTD reduced the intracellular triglyceride through depressing the mTOR pathway and affecting its downstream transcription factors.Keywords:dibutyltin dilaurate (DBTD);triglycerides metabolism;mTOR pathway;SREBP1C;PPARα
研究领域:
毒理学
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细胞生物学
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代谢研究
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DOI
PubMed
高影响因子
Food Bioscience
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2026
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IF 6.2
Haiwang Liu,Zhongyan Bao,Yu Gao,Fengqin Feng,Minjie Zhao,Qing Lv,Qian Yang,Xi Zhang
Drug-induced malnutrition resulting from long-term glucocorticoid therapy has increasingly become a clinical concern. Dietary-derived active peptides represent an effective nutritional intervention strategy, yet the specific mechanisms of action of albumin peptides (AP) remain unclear. This study systematically evaluated the therapeutic effects of AP in a Dexamethasone (DEX)-induced malnutrition mouse model and elucidated its mechanisms through integrated analyses of liver transcriptomics, non-targeted metabolomics, and quantitative fatty acid profiling. Results demonstrated that AP administration ameliorated DEX-induced protein catabolism, increased serum prealbumin (PAB) levels by 183.66%, elevated total protein (TP) levels by 14.6%, and significantly reversed hepatic steatosis and gastrocnemius muscle degeneration. Transcriptomic analysis revealed that peroxisome proliferator-activated receptor alpha (PPARα) was the primary signaling pathway affected by AP, with gene expression levels of Ppara and related genes restored to normal ranges. Non-targeted metabolomic analyses further identified correlations between this transcriptional response and prostaglandin, leukotriene, and diacylglycerol levels. Fatty acid quantification showed that AP restored hepatic arachidonic acid levels by 17.3%. Correlation analyses revealed a significant positive relationship between hepatic arachidonic acid levels and PPARα expression (R≥0.97), reinforcing the hypothesis that arachidonic acid serves as a key endogenous ligand mediating the interaction between AP and PPARα. Additionally, AP restored short-chain fatty acid concentrations in feces, indicating the pivotal role of the gut-liver axis in phenotypic development. Together, these findings suggest that AP alleviates DEX-induced malnutrition partly through restoration of hepatic arachidonic acid metabolism and reactivation of PPARα signaling, supporting its potential as a functional food ingredient for drug-induced malnutrition.
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高影响因子
Theranostics
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2026
·Vol. 16
·期 5
·2466
·
IF 13.3
Ming-Rui Zhai,Jie Pan,Zhen-Huan Wu,Yu-Ying He,Kai-Run Zhang,Long Ren,Yu-Rong Wang,Yi-Bing Li,Jun Gao,Lei Xiao,Yue-Hua Liu
Rationale: Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), has emerged as a risk factor for Parkinson's Disease (PD). Yet, whether CIH increases PD susceptibility and the underlying mechanisms remain elusive. Methods: To investigate the impact of CIH on PD susceptibility, we established a series of subtoxic PD models subjected to CIH conditions. We analyzed lipid metabolism, with a particular focus on lipid droplets (LDs), in the pathogenesis of CIH-induced PD. Furthermore, we examined the significance of LD-mitochondrial interactions in mediating aberrant LD accumulation within dopaminergic (DA) neurons and identified the tethering proteins implicated in this process. Additionally, we utilized both systemic and region-specific modulation of the peroxisome proliferator-activated receptor α (PPARα) pathway to assess the neuroprotective potential of restoring LD-mitochondrial coupling in PD models. Results: We revealed that CIH significantly exacerbated nigrostriatal DA neurodegeneration and motor dysfunction in subtoxic PD models. Mechanistically, we identified a PPARα-dependent disruption of Mfn2-Plin5 tethering, which impaired LD-mitochondrial interactions, thereby compromising LD turnover and promoting pathological LD accumulation within DA neurons. Crucially, pharmacological interventions targeting the LD-mitochondrial axis, including strategies to enhance LD catabolism, inhibit mitochondrial fission, or restore LD-mitochondrial tethering, effectively mitigated nigrostriatal DA neurodegeneration in CIH-preconditioned subtoxic PD models. Conclusions: This study reveals a previously unrecognized LD-mitochondrial regulatory axis underlying CIH-associated PD pathology and highlights its potential as a therapeutic target against CIH-accelerated neurodegeneration.
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PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
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IF 8.2
Xiaoyuan Wang,Yinchuan Lv,Xin Qiang,Shumin Liang,Ruosi Li,Jing Zhan,Jiaying Liu
The disruption of per- and polyfluoroalkyl substances (PFASs) on bile acid (BA) homeostasis has raised public concerns, making the evaluation of their effects and underlying mechanisms a high priority. Although the use of perfluorooctanoic acid (PFOA) has been restricted, it remains a widespread legacy PFAS in the environment. Concurrently, the use of its prevalent short-chain alternative, perfluorobutanoic acid (PFBA), is increasing, yet the toxicity assessment of PFBA remains inadequate. In this study, C57BL/6N mice were exposed to PFOA and PFBA (0.4 or 10 mg/kg body weight) by gavage for 28 days. The results showed that both PFOA and PFBA significantly increased hepatic weight, although PFBA exhibited lower bioaccumulation than PFOA in the liver. Targeted metabolomics revealed that PFOA significantly decreased total BA levels and altered their composition. Conversely, PFBA, without significantly altering total BA levels, notably changed their composition, such as increasing the proportion of cholic acid. Further investigations using in vivo and in vitro assays suggested that PFOA inhibited the expression of Cyp7A1, a key BA synthetase, potentially via PPARα activation, thereby reducing BA levels. In contrast, PFBA enhanced Cyp7A1 expression, associated with the inhibition of intestinal Farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) pathway. This study evaluated the differences in the BA-interfering effects of PFOA and PFBA and shed light on the potential mechanisms, which will provide new insights into the health risks of legacy PFASs and their alternatives.
研究领域:
毒理学
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环境健康
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代谢组学
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分子生物学
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PubMed
高影响因子
JOURNAL OF SOILS AND SEDIMENTS
·
2017
·Vol. 18
·期 3
·845-851
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IF 2.522
Guan Tianzhu,Sun Yonghai,Zhang Tiehua,Li Tiezhu,Li Zhuolin,Zhang Yue,Zhang Jie,Wang Yongjun
Purpose Extensive use of bisphenol A (BPA) and its analogues has caused increasing concern over the potential adverse health impacts of these chemicals. The aim of this study was to develop a fluorescence polarization (FP) assay to detect bisphenol A, bisphenol AF (BPAF), tetrabromobisphenol A (TBBPA), and tetrachlorobisphenol A (TCBPA) simultaneously. Materials and methods A recombinant peroxisome proliferator-activated receptor α ligand binding domain (mPPARα-LBD*) was chosen as recognition element in developed FP procedure. The environmental soil samples were assayed for (1) analytical parameters, (2) matrix effect, (3) recovery experiment, and (4) HPLC validation. For statistical analysis, GraphPad Prism 5 software was used. Results and discussion Under the optimized conditions, this assay had an IC 50 of 2.80, 6.84, 4.67, and 4.66 μg g −1 for BPA, BPAF, TBBPA, and TCBPA, respectively. The developed assay demonstrated the limits of detection (LODs) of 0.35, 0.21, 0.27, and 1.03 μg g −1 for these four compounds, which could meet the requirement of environmental monitoring. For spiked soil samples, mean recoveries of the analytes ranged from 85.3 to 101.1%, yielding coefficient of variations (CVs) ranged from 9.8 to 17.5%. Conclusions In this study, a broad-specificity receptor protein for BPA, BPAF, TBBPA, and TCBPA was produced and was used to develop an FP assay in soil samples. The efficiency and simplicity of the proposed assay define its possible application as a screening tool for environmental monitoring.
研究领域:
环境科学
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分析化学
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毒理学
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高影响因子
Frontiers in Veterinary Science
·
2025
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IF 2.9
Wenhao Tan,Kunyu Jiang,Yuhan Zhang,Hang Gao,Xingyi Tang,Sha Jiang
To investigate the effects of AdipoRon on fatty liver syndrome (FLS) in chicken, we used a corticosterone (CORT)-induced fatty liver model in Cobb broilers in vivo and fat emulsion-induced model in Leghorn male hepatoma cells (LMH) in vitro. In the in vivo study, eighteen 33-day-old male Cobb broilers were randomly assigned to three groups: control group (CONT, vehicle), corticosterone-treated group (CORT, 4 mg/kg), and corticosterone with AdipoRon-treated group (CORT-AR, 4 mg/kg and 0.2 mg/kg, 1 time/1 day) for 5 days. The results showed AdipoRon reduced CORT-induced increase in liver crude fat content (p < 0.05), increased protein expressions of peroxisome proliferator-activated receptor α (PPARα) (p < 0.05) and adiponectin (ADPN) (p < 0.05), and suppressed the protein expressions of Acetyl-CoA carboxylase 1 (ACC) (p < 0.05) and phosphorylated c-Jun N-terminal kinase 1 (p-JNK1) (p < 0.05) in the liver. In the in vitro study, LMH cells were divided into control (CN), fat emulsion (FE, 10%), and FE + AdipoRon (4 μM) group (FE-AR). AdipoRon reduced FE-induced lipid accumulation (p < 0.05), decreased the protein expression of ACC and tumor necrosis factor-alpha (TNF-α), and enhanced PPARα, the phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK), and carnitine palmitoyl transferase 1 (CPT-1) (p < 0.05). In conclusion, AdipoRon effectively reduces hepatic lipid deposition in CORT-induced FLS broilers, likely through PPARα activation and inhibition of lipid synthesis via ACC downregulation.
研究领域:
兽医学
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动物营养学
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分子生物学
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代谢病学
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药理学
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PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2021
·Vol. 35
·期 7
·3898-3915
·
IF 5.882
Li Zhang,Sheng-Ye Yang,Feng-Rong Qi-Li,Xiao-Xiao Liu,Wei-Tao Zhang,Chao Peng,Ping Wu,Ping Li,Pingping Li,Xiaojun Xu
Isoliquiritigenin (ISO) is a flavonoid extracted from the root of licorice, which serves various biological and pharmacological functions including antiinflammatory, antioxidation, liver protection, and heart protection. However, the mechanism of its action remains elusive and the direct target proteins of ISO have not been identified so far. Through cell-based screening, we identified ISO as a potent lipid-lowering compound. ISO treatment successfully ameliorated fatty acid-induced cellular lipid accumulation and improved nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) by increasing PPARα-dependent lipid oxidation and decreasing SREBPs-dependent lipid synthesis. Both these signaling required the activation of SIRT1. Knockdown of SIRT1 resulted in the reversal of ISO beneficiary effects suggesting that the lipid-lowering activity of ISO was regulated by SIRT1 expression. To identify the direct target of ISO, limited proteolysis combined with mass spectrometry (LiP-SMap) strategy was applied and IQGAP2 was identified as the direct target for ISO in regulating lipid homeostasis. In the presence of ISO, both mRNA and protein levels of SIRT1 were increased; however, this effect was abolished by blocking IQGAP2 expression using siRNA. To explore how IQGAP2 regulated the expression level of SIRT1, proteome profiler human phospho-kinase array kit was used to reveal possible phosphorylated kinases and signaling nodes that ISO affected. We found that through phosphorylation of CREB, ISO transduced signals from IQGAP2 to upregulate SIRT1 expression. Thus, we not only demonstrated the molecular basis of ISO in regulating lipid metabolism but also exhibited for the first time a novel IQGAP2-CREB-SIRT1 axis in treating NAFLD/NASH.
研究领域:
药理学
·
分子生物学
·
肝病学
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PubMed
高影响因子
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