BIOMEDICINE & PHARMACOTHERAPY
·
2020
·
IF 4.545
Zhishen Xie,Jianping Zhao,Hui Wang,Yali Jiang,Qiaoling Yang,Yu Fu,Huahui Zeng,Christian Hölscher,Jiangyan Xu,Zhenqiang Zhang
This study aims to investigate whether magnolol (MG), a natural neolignane compound, can prevent AD induced by beta-amyloid (Aβ) and the possible mechanisms involved. MG dose-dependently reduces Aβ deposition, toxicity and memory impairment caused by Aβ in transgenic C. elegans . More importantly, these effects are reversed by GW9662, a selective peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist. MG is more effective in enhancing PPAR-γ luciferase levels than honokiol (HK). Meanwhile, MG has the potential to bind with the ligand binding domain of PPAR-γ (PPAR-γ-LBD). As expected, MG inhibited the luciferase activity of NF-κB and its target genes of inflammatory cytokines, and this effect was blocked by GW9662. The luciferase activity of Nrf2-ARE expression can be activated by MG and decreased Aβ-induced reactive oxygen species (ROS). The target gene LXR of PPAR-γ is activated by MG, which upregulates ApoE and promotes microglia phagocytosis and the degradation of Aβ, and these effects were also reversed by GW9662. In summary, MG can attenuate Aβ-induced AD and the underlying mechanism is the reduction of inflammation and promotion of phagocytosis and degradation of Aβ, which is dependent on PPAR-γ.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Xiaoping Liang,Jiehua Liang,Shengqi Zhang,Haowei Yan,Tiangang Luan
Di-2-ethylhexyl phthalate (DEHP), a widely utilized plasticizer , has been described as a potential obesogen based on in vivo disruption of hepatic lipid homeostasis and in vitro promotion of lipid accumulation. However, limited literature exists regarding the specific ramifications of DEHP exposure on obese individuals, and the precise mechanisms underlying the adverse effects of DEHP exposure remain unclear. This study aimed to assess the impact of DEHP on hepatic lipid metabolism in obese mice by comparing them to normal mice. Following a 10-week DEHP exposure period, the obese mice exhibited higher blood lipid levels, more severe hepatic steatosis, and more infiltrations of inflammatory cells in liver tissue than normal mice. Interestingly, the body weight of the mice exhibited no significant alteration. In addition, transcriptomic analyses revealed that both lipogenesis and fatty acid oxidation contributed to hepatic lipid metabolism dysregulation following DEHP exposure. More specifically, alterations in the transcription of genes associated with hepatic lipid metabolism were linked to the different responses to DEHP exposure observed in normal and obese mice. Additionally, the outcomes of in vitro experiments validated the in vivo findings and demonstrated that DEHP exposure could modify hepatic lipid metabolism in normal mice by activating the LXR/SREBP-1c signaling pathway to promote lipogenesis. At the same time, DEHP exposure led to inhibition of the Camkkβ/AMPK pathway to suppress β -fatty acid oxidation. Conversely, in obese mice, DEHP exposure was found to be associated with the stimulation of both lipogenesis and fatty acid oxidation via activation of the LXR/SREBP-1c and PPAR-α signaling pathways, respectively. The findings presented in this study first elucidate the contrasting mechanisms underlying DEHP-induced liver damage in obese and normal mice, thereby offering valuable insights into the pathogenesis of DEHP-induced liver damage in individuals with obesity.
研究领域:
毒理学
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肝病学
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分子生物学
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肥胖研究
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2022
·
IF 10.753
Qiaoqiao Wang,Jingjing Miao,Anran Zhao,Manni Wu,Luqing Pan
Retinoid X receptor (RXR) and peroxisome proliferators-activated receptors (PPAR) have been shown as important targets of endocrine disrupting effects caused by organotin compounds (OTCs). In vitro methods for non-model species are instrumental in revealing not only mechanism of toxicity but also basic biology. In the present study, we constructed the GAL4 factor-based recombinant yeast systems of RXRα/RXRα (RR), RXRα/PPARα (RPα) and RXRα/PPARγ (RPγ) of the scallop Chlamys farreri to investigate their transcriptional activity under the induction of OTCs (tributyltin chloride, triphenyltin chloride, tripropyltin chloride and bis(tributyltin)oxide), their spiked sediments and five other non‑tin compounds (Wy14643, rosiglitazone, benzyl butyl phthalate, dicyclohexyl phthalate and bis(2-ethylhexyl) phthalate). The results showed that the natural ligand of RXR, 9-cis-retinoic acid (9cRA), induces transcriptional activity in all three systems, while four OTCs induced the transcriptional activity of the RR and RPα systems. None of the five potential non‑tin endocrine disruptors induced effects on the RPα and RPγ systems. The spiked sediment experiment demonstrated the feasibility of the recombinant yeast systems constructed in this study for environmental sample detection. These results suggest that OTCs pose a threat to affect function of RXRα and PPARα of bivalve mollusks. The newly developed GAL4 factor-based yeast two-hybrid system can be used as a valuable tool for identification and quantification of compounds active in disturbing RXR and PPAR of bivalves.
研究领域:
环境毒理学
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分子生物学
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水生生态学
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产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2018
·Vol. 46
·期 11
·1538-1545
·
IF 3.64
Jiangming Deng,Lianxia Guo,Baojian Wu
Human CYP2A6 (Cyp2a5 in mice) plays an important role in metabolism and detoxification of various drugs and chemicals. Here, we investigated a potential role of peroxisome proliferator-activated receptor γ (Ppar-γ) in circadian regulation of the Cyp2a5 enzyme. We first showed that Cyp2a5 mRNA and protein in mouse liver displayed robust circadian oscillations. Consistent with a circadian protein pattern, Cyp2a5-mediated 7-hydroxylation of coumarin was circadian time–dependent. Formation of 7-hydroxycoumarin was more extensive at a dosing time of Zeitgeber time 2 (ZT2) than that at ZT14. Interestingly, the nuclear receptor Ppar-γ was also a circadian gene. Circadian Ppar-γ protein level was strongly correlated with the Cyp2a5 mRNA level (r = 0.989). Furthermore, Ppar-γ activation (by a selective agonist, rosiglitazone) upregulated Cyp2a5 expression in Hepa-1c1c7 cells, whereas Ppar-γ knockdown downregulated Cyp2a5 expression. Also, Ppar-γ knockdown blunted the rhythmicity of Cyp2a5 mRNA in serum-shocked Hepa-1c1c7 cells. In addition, a combination of promoter truncation analysis, mobility shift, and chromatin immunoprecipitation assays revealed that Ppar-γ directly bound to a PPAR response element (i.e., the −1418- to −1396-bp region) within Cyp2a5 promoter and activated the gene transcription. Taken together, Ppar-γ was a transcriptional activator of Cyp2a5, and its rhythmic expression contributed to circadian expression of Cyp2a5.
研究领域:
药理学
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分子生物学
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昼夜节律生物学
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DOI
PubMed
高影响因子
NEUROTOXICOLOGY
·
2022
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IF 4.398
Xiaoyu Qu,Jie Ma,Huan Gao,Yueming Zhang,Jinghui Zhai,Jiawei Gong,Yanqing Song,Tingting Hu
Isoniazid (INH) and rifampicin (RIF) are co-administered in tuberculosis treatment but can cause neurotoxicity , and the mechanism is not known. To explore this mechanism, we employed an integrated approach using metabolomics analysis (MA) and proteomics analysis (PA). Male mice were divided into three groups and administered vehicle (control group), or co-administered INH (120 mg/kg) and RIF (240 mg/kg), for 7 or 14 days. Mice brains were collected for mass spectrometry-based PA and MA plus lipidomics analysis. Measurement of brain levels of malondialdehyde and superoxide dismutase revealed time-dependent brain injury after exposure to INH+RIF for 7 and 14 days. Also, 422 proteins, 35 metabolites, and 21 lipids were dysregulated and identified. MA demonstrated “purine metabolism,” “phenylalanine, tyrosine and tryptophan biosynthesis,” “biosynthesis of unsaturated fatty acids ,” “phenylalanine metabolism,” and “arginine biosynthesis” to be disturbed significantly. PA demonstrated pathways such as “lipids,” “amino acids,” and “energy metabolism” to be disrupted. Peroxisome proliferator-activated receptor (PPAR) pathways were changed in energy metabolism, which led to the neurotoxicity induced by INH+RIF. Immunohistochemical analyses of PPARs in mice brains verified that PPAR-α and -γ expression was downregulated. PPAR-α and -γ activation might be a key target for alleviating INH+RIF-induced neurotoxicity.
研究领域:
药理学
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毒理学
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神经科学
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生物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Biology-Basel
·
2026
·Vol. 15
·期 4
·347
·
IF 4.3
Wael Ennab,Saber Y. Adam,Hao-Yu Liu,Ghaid J. Al-Rabadi,Ping Hu,Baiome Abdelmaguid Baiome,Kaiqi Li,Abdelkareem A. Ahmed,In Ho Kim,Madesh Muniyappan,Demin Cai
Simple SummaryT-2 toxin, a widespread mycotoxin, induces hepatotoxicity and gut dysbiosis, with limited mitigation strategies. This study demonstrates that lycopene protects against T-2 mycotoxicosis in mice by integrating microbiota restoration with hepatic metabolic reprogramming. Lycopene suppressed pro-inflammatory cytokines, alleviated oxidative stress, and enriched beneficial Muribaculum while suppressing pathogenic Escherichia. Mechanistically, lycopene de-repressed Peroxisome proliferator-activated receptor (PPAR) signaling and restored fatty acid oxidation and phase I detoxification gene expression. A hormetic dose–response was evident: low-dose lycopene outperformed high-dose lycopene, underscoring non-linear efficacy. These findings position lycopene as a candidate feed additive targeting the gut–liver–PPAR axis, though dose optimization remains critical for translation.Exposure to T2 toxin is known to induce hepatotoxicity and gut dysbiosis, yet effective dietary interventions remain underexplored. This study investigates the hepatoprotective and microbiota-modulating effects of lycopene against T2 toxin-induced toxicity in mice. Mice were exposed to T2 toxin with or without lycopene supplementation at low and high doses. The hepatic function, oxidative stress markers, inflammatory gene expression, detoxification pathway activity, and gut microbiota composition were assessed using histological, biochemical, and molecular analyses. T2 toxin exposure resulted in significant weight loss, oxidative liver damage, and gut dysbiosis—marked by a decline in beneficial phyla and an increase in pathogenic bacteria. Hepatic injury was accompanied by upregulated pro-inflammatory genes and downregulated PPAR pathway genes, leading to impaired lipid metabolism and disrupted liver histology. Lycopene supplementation effectively attenuated these effects: it reduced oxidative stress, enhanced antioxidant defense, lowered inflammatory markers, and restored gut microbial balance. Furthermore, lycopene upregulated PPAR pathway and phase I detoxification genes. Notably, the low-dose lycopene regimen demonstrated superior efficacy compared to the high-dose regimen. In conclusion, lycopene, particularly at a low dose, confers significant protection against T2 toxin-induced hepatotoxicity and gut dysbiosis, highlighting its potential as a dietary strategy for mitigating mycotoxin-induced health risks.
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产品关联
DOI
PubMed
高影响因子
MEDICINAL CHEMISTRY RESEARCH
·
2024
·Vol. 33
·期 5
·796-810
·
IF 2.6
Quan Lina,Guo Ying,Wang Siyao,Sun Mengfei,Pang Yan,Cui Chunli,Wang Jinrui,Wei Jinlian,Wei Peifeng,Xie Yundong
Molecular hybridization method was applied to design and synthesize a series of target compounds paeonol-based fibrate derivatives. The target compound was screened using a Triton WR-1339 induced hyperlipidemia mouse model, and compound T9 was found to have good lipid-lowering activity. The dose-dependent study of its lipid-lowering activity was also conducted. To further evaluate the lipid-lowering activity of compound T9, a hyperlipidemic mouse model induced by high fat emulsion can be used. The findings of the research illustrate that T9 is capable of significantly decreasing blood lipid levels, including TG, TC, LDL-C, and increasing HDL-C. The results of liver tissue oil red O staining and HE staining demonstrated that T9 improved the hepatic lipid accumulation, thus decreasing AST and ALT levels and protecting against hyperlipidemic liver injury. Studies into the lipid-lowering effect of T9 have indicated that it can upregulate PPAR-α protein expression in liver tissue, while simultaneously decreasing the expression of HMG-CoA protein. T9 was further demonstrated to possess antioxidant properties, as evidenced by an increase in SOD and a decrease in MDA, as well as anti-inflammatory effects, demonstrated by a decrease in TNF-α, IL-1β, and IL-6, thus confirming its potential as a hypolipidemia and hepatoprotective agent. Graphical Abstract
研究领域:
药理学
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分子生物学
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产品关联
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2018
·
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
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Toxics
·
2023
·Vol. 11
·期 2
·184
·
IF 4.6
Huazhong Zhang,Jinsong Zhang,Jinquan Li,Zhengsheng Mao,Jian Qian,Cheng Zong,Hao Sun,Beilei Yuan
Diquat (DQ), a widely used bipyridyl herbicide, is associated with significantly higher rates of kidney injuries compared to other pesticides. However, the underlying molecular mechanisms are largely unknown. In this study, we identified the molecular changes in the early stage of DQ-induced kidney damage in a mouse model through transcriptomic, proteomic and metabolomic analyses. We identified 869 genes, 351 proteins and 96 metabolites that were differentially expressed in the DQ-treated mice relative to the control mice (p< 0.05), and showed significant enrichment in the PPAR signaling pathway and fatty acid metabolism. Hmgcs2, Cyp4a10, Cyp4a14 and Lpl were identified as the major proteins/genes associated with DQ-induced kidney damage. In addition, eicosapentaenoic acid, linoleic acid, palmitic acid and (R)-3-hydroxybutyric acid were the major metabolites related to DQ-induced kidney injury. Overall, the multi-omics analysis showed that DQ-induced kidney damage is associated with dysregulation of the PPAR signaling pathway, and an aberrant increase in Hmgcs2 expression and 3-hydroxybutyric acid levels. Our findings provide new insights into the molecular basis of DQ-induced early kidney damage.Keywords:diquat;kidney injury;multi-omics;fatty acid metabolism;PPAR signaling pathway
研究领域:
毒理学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Food Chemistry: Molecular Sciences
·
2025
·
IF 4.7
Rabia Durrani,Sun Yutian,Hou Bowen,Hammad Ullah,Erwann Durand,Yang Meiyun,Long Yiyang,André Delavault,Muhammad Yasir,Huan Weiwei,Gao Fei,Song Lili
Plant-derived bioactive peptides have drawn increasing attention in the field of nutrition and food science due to their biological activities, low cost, safety, and ease of industrial production. Functional peptides from Torreya grandis are being investigated due to their potential as dietary supplements. This study focuses on T. grandis nut peptides that regulate LIPID-II inhibitor in mice fed a high-fat diet. Proteome analysis identified a Vicilin -like antimicrobial peptide involved in host defense. 16S rRNA Sequencing revealed alteration in gut microbiota with T. grandis administration as manifested by increased Akkermansia and Parabacteroides concurrently by decreased Firmicutes . Beneficial bacteria i.e., Akkermansia improved intestinal functions and increased levels of short chain fatty acids (SCFAs). T. grandis supplementation in HFD mice reduced body weight, TC, TG, LDL, and decreased inflammation, while reducing oxidative stress and increasing HDL in the model group fed a high-fat diet. Lipid droplets in liver, muscles, and blood vessels were highly reduced, evoked by the high peptide group. Transcriptome analysis highlighted lipid regulation via the PPAR-α pathway, with molecular docking revealing 4 potential lipid II inhibitory peptides. These findings suggested T. grandis as a promising supplement in food and a key nut for nutraceutical purposes.
研究领域:
营养与食品科学
·
微生物学
·
生物化学与分子生物学
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产品关联
DOI
PubMed
高影响因子
Current Computer-Aided Drug Design
·
2024
·
IF 1.5
Lingxiao Zhang,Chenghao Yang,Xinyue Ding,Hui Zhang,Yuling Luan,Yueer Tang,Zongjun Liu
Background: Berberine (BBR), also known as berberine hydrochloride, was isolated from the rhizomes of the Coptis chinensis. Studies have reported that BBR plays an important role in glycolipid metabolism, including insulin (IR). The targets, and molecular mechanisms of BBR against hyperlipid-induced IR is worthy to be further studied. Material and methods: The related targets of BBR were identified via Pharmmapper database and relevant targets of diabetes were obtained through GeneCards and Online Mendelian Inheritance in Man (OMIM) database. The common targets were employed with the STRING database and visualized with the protein-protein interactions (PPI) network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed to explore the biological progress and pathways. In vitro, human hepatocellular carcinomas (HepG2) cell was used as experimental cell line, and an insulin resistant HepG2 cell model (IR-HepG2) was constructed using free fatty acid induction. After intervention with BBR, glucose consumption and uptake in HepG2 cells were observed. Molecular docking was used to test the interaction between BBR and key targets, and real-time fluorescence quantitative PCR was used to detect the regulatory effect of BBR on related targets. Results: 262 overlapped targets were extracted from BBR and diabetes. In the KEGG enrichment analysis, the peroxisome proliferator activated receptor (PPAR) signaling pathway was included. In vitro experiments, BBR can significantly increase sugar consumption and uptake in IR HepG2 cells, while PPAR inhibitors can weaken the effect of BBR on IR-HepG2. Conclusion: The PPAR signaling pathway is one of the important pathways for BBR to improve high-fat-induced insulin resistance in HepG2 cells.
研究领域:
药理学
·
分子生物学
·
内分泌学
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转化医学
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代谢疾病研究
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DOI
PubMed
高影响因子
International Journal of Oral Science
·
2023
·Vol. 15
·期 1
·1-13
·
IF 14.9
Lan Tingting,Bi Fei,Xu Yuchan,Yin Xiaoli,Chen Jie,Han Xue,Guo Weihua
Xenogenic organ transplantation has been considered the most promising strategy in providing possible substitutes with the physiological function of the failing organs as well as solving the problem of insufficient donor sources. However, the xenograft, suffered from immune rejection and ischemia-reperfusion injury (IRI), causes massive reactive oxygen species (ROS) expression and the subsequent cell apoptosis, leading to the xenograft failure. Our previous study found a positive role of PPAR-γ in anti-inflammation through its immunomodulation effects, which inspires us to apply PPAR-γ agonist rosiglitazone (RSG) to address survival issue of xenograft with the potential to eliminate the excessive ROS. In this study, xenogenic bioroot was constructed by wrapping the dental follicle cells (DFC) with porcine extracellular matrix (pECM). The hydrogen peroxide (H 2 O 2 )-induced DFC was pretreated with RSG to observe its protection on the damaged biological function. Immunoflourescence staining and transmission electron microscope were used to detect the intracellular ROS level. SD rat orthotopic transplantation model and superoxide dismutase 1 (SOD1) knockout mice subcutaneous transplantation model were applied to explore the regenerative outcome of the xenograft. It showed that RSG pretreatment significantly reduced the adverse effects of H 2 O 2 on DFC with decreased intracellular ROS expression and alleviated mitochondrial damage. In vivo results confirmed RSG administration substantially enhanced the host’s antioxidant capacity with reduced osteoclasts formation and increased periodontal ligament-like tissue regeneration efficiency, maximumly maintaining the xenograft function. We considered that RSG preconditioning could preserve the biological properties of the transplanted stem cells under oxidative stress (OS) microenvironment and promote organ regeneration by attenuating the inflammatory reaction and OS injury.
研究领域:
移植学
·
再生医学
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药理学
·
细胞生物学
·
牙科学
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DOI
PubMed
高影响因子
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