JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2025
·Vol. 29
·期 9
·e70416
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IF 4.2
Xiliang Zhu,Qi Liu,Zhaoyun Cheng,Yi Luo
Bisphenol A (BPA) is a widely used industrial chemical with potential endocrine-disrupting effects on metabolic processes. This study investigates the impact of BPA on hepatic function and transcriptional regulation in mouse livers and AML12 cells. Male mice were exposed to low (5 g/kg) and high (50 g/kg) doses of BPA for six weeks. Transcriptomic analysis was performed on liver tissues, and histological examinations were conducted. AML12 cells were treated with varying BPA concentrations, and PPARG transcriptional activity was assessed using a luciferase reporter assay. Additionally, molecular docking, molecular dynamics (MD) simulations, drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), MM-PBSA calculations, and multi-species protein structure comparative analysis were employed to analyse the interaction between BPA and PPARG. Transcriptomic analysis revealed a decrease in differentially expressed genes with higher BPA doses, with low-dose exposure significantly downregulating hepatic Cpt1a mRNA levels. Histological examination indicated lipid vacuole formation at high doses without collagen deposition. BPA consistently inhibited PPARG activity in both MCF7 cells and mouse livers. BPA exposure disrupts hepatic lipid metabolism and PPARG activity, highlighting its role as an endocrine disruptor. Further research is needed to elucidate the long-term effects of BPA on liver health.
研究领域:
毒理学
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分子生物学
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代谢研究
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PubMed
高影响因子
JOURNAL OF AUTOIMMUNITY
·
2024
·
IF 7.9
Qishun Geng,Jiahe Xu,Xiaoxue Cao,Zhaoran Wang,Yi Jiao,Wenya Diao,Xing Wang,Zihan Wang,Mengxiao Zhang,Lu Zhao,Lei Yang,Tingting Deng,Bifa Fan,Yuan Xu,Lansi Jia,Cheng Xiao
Introduction Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by joint inflammation and bone damage, that not only restricts patient activity but also tends to be accompanied by a series of complications, seriously affecting patient prognosis. Peroxisome proliferator-activated receptor gamma (PPARG), a receptor that controls cellular metabolism, regulates the function of immune cells and stromal cells. Previous studies have shown that PPARG is closely related to the regulation of inflammation. However, the role of PPARG in regulating the pathological processes of RA is poorly understood. Materials and methods PPARG expression was examined in the synovial tissues and peripheral blood mononuclear cells (PBMCs) from RA patients and the paw of collagen-induced arthritis (CIA) model rats. Molecular biology experiments were designed to examine the effect of PPARG and cannabidiol (CBD) on RAW264.7 cells and CIA rats. Results The results reveal that PPARG accelerates reactive oxygen species (ROS) clearance by promoting autophagy, thereby inhibiting ROS-mediated macrophage polarization and NLRP3 inflammasome activation. Notably, CBD may be a promising candidate for understanding the mechanism by which PPARG regulates autophagy-mediated inflammation. Conclusions Taken together, these findings indicate that PPARG may have a role for distinguishing between RA patients and healthy control, and for distinguishing RA activity; moreover, PPARG could be a novel pharmacological target for alleviating RA through the mediation of autophagy. CBD can act as a PPARG agonist that alleviates the inflammatory progression of RA.
研究领域:
免疫学
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风湿病学
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药理学
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细胞生物学
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SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
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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PubMed
高影响因子
BIOLOGICAL RESEARCH
·
2026
·
IF 5.4
Ying Shen,Xiaolin Gao,Jiashi Wang,Yingying Hao
Background: Abnormal syncytialization of cytotrophoblast (CTB) cells is known to be associated with preeclampsia (PE), however, the underlying molecular mechanisms remain elusive. Results: In this study, proteomic analysis of placental tissues was performed to identify proteins involved in PE pathogenesis. NCK Adaptor Protein 1 (NCK1) was found to be downregulated in placental tissues from patients with early-onset PE. In vitro functional assays revealed that NCK1 was markedly increased during spontaneous syncytialization of CTB cells. NCK1 overexpression alleviated hypoxia-induced defects in CTB cell fusion. Mechanistically, NCK1 upregulated both the expression and stability of Peroxisome Proliferator-Activated Receptor Gamma (PPARG), accompanied by increased m6A modification of its mRNA. Overexpression of PPARG significantly rescued hypoxia-induced syncytialization impairment, whereas PPARG deficiency abolished the promotive effects of NCK1 on CTB syncytialization. Additionally, phosphorylation of Eukaryotic Translation Initiation Factor 3 Subunit (EIF3D) was significantly increased during spontaneous syncytialization, and NCK1 overexpression partially reversed hypoxia-induced suppression of EIF3D phosphorylation. EIF3D knockdown significantly reduced m6A levels on PPARG mRNA, likely due to impaired NCK1-mediated suppression of Alpha-Ketoglutarate-Dependent Homolog 5 (ALKBH5), an m6A demethylase. Furthermore, NCK1 enhanced EIF3D phosphorylation by inhibiting its O-GlcNAcylation. Conclusions: Our findings demonstrate that NCK1 stabilizes PPARG by modulating the crosstalk between O-GlcNAcylation and phosphorylation of EIF3D, thereby restoring hypoxia-impaired syncytialization in CTB cells. This study identifies the NCK1/EIF3D/PPARG axis as a molecular pathway potentially relevant to trophoblast fusion dysfunction in PE.
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Biomed Research International
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2022
·
IF 3.246
Shisheng Jiang,Chaoming Huang,Shulin Wang,Biyun Huang,Dan Wu,Guodong Zheng,Yi Cai
Objective. Through a network pharmacology method, we screened the main active compounds of Citri Reticulatae Pericarpium (CRP), constructed a drug-ingredient-disease-target network, explored the molecular mechanism of its treatment of myocardial hypertrophy, and validated it by using molecular biology approach. Methods. Traditional Chinese Medicine Systems Pharmacology (TCMSP) and GeneCards were utilised to collect the effective component in CRP and the targets of CRP and myocardial hypertrophy. The STRING database constructed the protein interaction network. The drug-ingredient-disease-target network was outlined by the Cytoscape 3.9.0 software. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using the Metascape database. Real-time PCR (RT-PCR) and Western blotting were utilised to determine the mRNA and protein level of the critical targets of CRP therapy for myocardial hypertrophy. Results. We found that five practical components of CRP exerted therapeutic effects on myocardial hypertrophy by modulating 41 targets. Further analysis revealed that naringenin was the essential active compound in CRP that regulated myocardial hypertrophy. In addition, we showed that the active compounds of CRP might exert antihypertrophy effects via regulating essential target proteins such as AKT1-, MAPK3-, PPARA-, PPARG-, and ESR1-mediated signaling pathways such as cell proliferation, nuclear receptor activation, and oxidative stress. The molecular biology experiments demonstrated that naringenin inhibited the mRNA level of NPPA and NPPB induced by Ang II and regulated related targets such as AKT1, MAPK3, PPARA, PPARG, and ESR1. Conclusion. CRP could inhibit myocardial hypertrophy through multitarget and multiapproach.
研究领域:
药理学
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分子生物学
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中医药学
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心脏病学
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PubMed
高影响因子
Pharmaceuticals
·
2025
·Vol. 18
·期 11
·1759
·
IF 4.8
Jing Hong,Fangyu Zhang,Ruizhen Zhang,Hongyang Fu,Dongang Shen,Xinyue Wang,Yuting Yang,Jiamei Wu,Lin Meng,Hongyang Lü,Xiwei Jiang,Yunli Zhao
Background: Doxorubicin (DOX) is a highly effective chemotherapy drug, but its use is limited by dose-dependent cardiotoxicity, driving the search for protective natural products. Although the herb Viscum coloratum (Kom.) Nakai is known for its cardiovascular benefits, the cardioprotective effects and mechanisms of its isolated compound, DHDK, remain unexplored. Methods: The protective effect of DHDK was first evaluated in DOX-injured H9c2 cardiomyocytes. Subsequently, an integrated network toxicology (incorporating DOX-induced toxicity targets and relevant chronic disease pathways such as aging and lipid metabolism) and pharmacology (DHDK) approach identified core targets, which were then refined through Protein–Protein Interaction (PPI) analysis and molecular docking. The underlying mechanism was investigated using lipidomics and validated through a series of in vitro assays, including CCK-8, q-PCR, biochemical tests, and flow cytometry, as well as in an in vivo rat model. Results: DHDK significantly alleviated DOX-induced cardiomyocyte toxicity. Integrated analysis identified 56 intersecting targets, with PPARG confirmed as the primary target via PPI and molecular docking. Lipidomics revealed that DHDK potently attenuated DOX-induced accumulation of pathogenic lipids (e.g., fatty acids, ceramides). Mechanistically, DHDK activated PPARG, which in turn upregulated CPT1B, a key regulator of fatty acid β-oxidation (FAO). This enhanced cell viability, ATP production, and mitochondrial membrane potential while reducing oxidative stress. These protective effects, which were abolished by the inhibition of PPARG or CPT1B, were further validated in vivo. Conclusion: This study demonstrates that DHDK exerts its cardioprotective effect by activating the PPARG-CPT1B-FAO axis, effectively correcting lipid metabolic disorders. Given that lipid dysregulation is a hallmark of various internal metabolic diseases, DHDK may also hold therapeutic potential for other heart conditions driven by metabolic disturbances, such as diabetic cardiomyopathy, highlighting its broad relevance to the field of internal diseases.
研究领域:
药理学
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肿瘤心脏病学
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代谢组学
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天然产物化学
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分子生物学
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毒理学
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脂质组学
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PubMed
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Iranian Journal of Basic Medical Sciences
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2022
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IF 2.532
Hongxia Wang,Zhiyu Shao,Zhiwen Xu,Binghao Ye,Ming Li,Qiaoqiao Zheng,Xingyuan Ma,Ping Shi
Objective(s): Gemcitabine is a first-line drug for the treatment of bladder cancer. One of the most important mechanisms of gemcitabine resistance is the low expression of cellular membrane transporter hENT1. Various derivatives containing fatty acid side chains have been developed in order to facilitate gemcitabine uptake and prolong its retention in cells, such as CP-4126. In this study, the anti-tumor effect and mechanism of a new derivative of gemcitabine named SZY-200 on bladder cancer cells were investigated. SZY-200 was assembled from the gemcitabine-lauric acid conjugate. Materials and Methods: Antiproliferative activities of SZY-200 and lauric acid were evaluated using CCK-8 assay and clonogenic survival assay. The hENT1 inhibitor NBMPR was employed to determine the role of hENT1 in the apoptotic activity of GEM, CP-4126, and SZY-200. RT-qPCR, flow cytometry, fluorescence microscope, western blotting, and wound healing assay were used to study the mechanisms of SZY-200. The target genes were predicted using the BATMAN-TCM database. Results: Our data showed that SZY-200 could inhibit the proliferation of bladder cancer cells by inducing cell cycle arrest and apoptosis. The inhibitory effects were comparable to gemcitabine and CP-4126. SZY-200 does not rely on hENT1 to help it enter bladder cancer cells. Also, we found that lauric acid could inhibit the proliferation of bladder cancer cells. SZY-200 could down-regulate the expressions of PPARG and PTGS2 which were related to the occurrence and development of bladder cancer. Conclusion: SZY-200 has the same or more advantages as CP-4126 and could be an ideal candidate drug for further in vivo investigation.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症研究
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高影响因子
Frontiers in Pharmacology
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2023
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IF 5.6
Yunsheng Ran,Chujiao Hu,Junzhao Wan,Qian Kang,Ruixian Zhou,Ping Liu,Dan Ma,Jianta Wang,Lei Tang
Peroxisome proliferator-activated receptor gamma (PPARG), a key transcription factor involved in lipid metabolism and glucose homeostasis, has been implicated in various types of cancer. However, its precise role in cancer remains unclear. In this study, we conducted a comprehensive pan-cancer analysis of PPARG expression using various types of cancer obtained from public databases. We observed significant heterogeneity in PPARG expression across different types of cancer. The association between PPARG expression and patient prognosis was investigated using Cox proportional hazards regression models and survival analysis. Clinical features and protein expression levels in the cohort showed that PPARG expression was strongly associated, suggesting its potential as a therapeutic target. We also evaluated the prognostic potential of PPARG by analyzing immune infiltration and genomic stability. We experimentally validated the potential of PPARG as a therapeutic target by analyzing drug sensitivity profiles, molecular docking simulations, and in vitro cell proliferation assays associated with PPARG expression. We identified common expression patterns of PPARG with other genes involved in key carcinogenic pathways. This provides deeper insights into the molecular mechanisms underlying its carcinogenic role. Additionally, functional enrichment analysis revealed significant enrichment of genes related to drug metabolism, cell proliferation, and immune response pathways associated with PPARG. Our findings highlight the importance of PPARG in the broader biology of cancer and suggest its potential as a diagnostic and therapeutic target for specific types of cancer. The results of our study provide strong support for the potential role of PPARG as a promising prognostic biomarker and immunotherapeutic target across various types of cancer.
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Journal of Translational Medicine
·
2023
·Vol. 21
·期 1
·1-14
·
IF 7.4
Chen Shengnan,Li Bo,Chen Lei,Jiang Hongli
Background Diabetic kidney disease (DKD) has been the leading cause of chronic kidney disease in developed countries. Evidence of the benefits of resveratrol (RES) for the treatment of DKD is accumulating. However, comprehensive therapeutic targets and underlying mechanisms through which RES exerts its effects against DKD are limited.Methods Drug targets of RES were obtained from Drugbank and SwissTargetPrediction Databases. Disease targets of DKD were obtained from DisGeNET, Genecards, and Therapeutic Target Database. Therapeutic targets for RES against DKD were identified by intersecting the drug targets and disease targets. GO functional enrichment analysis, KEGG pathway analysis, and disease association analysis were performed using the DAVID database and visualized by Cytoscape software. Molecular docking validation of the binding capacity between RES and targets was performed by UCSF Chimera software and SwissDock webserver. The high glucose (HG)-induced podocyte injury model, RT-qPCR, and western blot were used to verify the reliability of the effects of RES on target proteins.Results After the intersection of the 86 drug targets and 566 disease targets, 25 therapeutic targets for RES against DKD were obtained. And the target proteins were classified into 6 functional categories. A total of 11 cellular components terms and 27 diseases, and the top 20 enriched biological processes, molecular functions, and KEGG pathways potentially involved in the RES action against DKD were recorded. Molecular docking studies showed that RES had a strong binding affinity toward PPARA, ESR1, SLC2A1, SHBG, AR, AKR1B1, PPARG, IGF1R, RELA, PIK3CA, MMP9, AKT1, INSR, MMP2, TTR, and CYP2C9 domains. The HG-induced podocyte injury model was successfully constructed and validated by RT-qPCR and western blot. RES treatment was able to reverse the abnormal gene expression of PPARA, SHBG, AKR1B1, PPARG, IGF1R, MMP9, AKT1, and INSR.Conclusion sRES may target PPARA, SHBG, AKR1B1, PPARG, IGF1R, MMP9, AKT1, and INSR domains to act as a therapeutic agent for DKD. These findings comprehensively reveal the potential therapeutic targets for RES against DKD and provide theoretical bases for the clinical application of RES in the treatment of DKD.
研究领域:
药理学
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分子生物学
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糖尿病
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肾病学
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PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2026
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IF 3.2
Yuxing Liao,Huiqing Liang,Hongmei Huang,Wenjie Yang,Shuangyan Su,Cuixiang Zhang,Yuxi Xiao,Jiaqi Gong,Qirong Yang,Guihua Wang,Guiyuan Chen,Xueying Li
PPARG identified as shared core target of DEHP and MEHP in HCC via network toxicology. • PPARG upregulation linked to poor overall survival in hepatocellular carcinoma. • DEHP/MEHP exposure induces lipid accumulation and PPARG expression in HepG2 cells. • Metabolomics reveals phthalate-induced disruptions in lipid and nucleotide pathways. Di(2-ethylhexyl) phthalate (DEHP) and its primary metabolite mono(2-ethylhexyl) phthalate (MEHP) have been implicated in metabolic dysregulation and carcinogenesis, but their potential links to hepatocellular carcinoma (HCC) remain unclear. Using network toxicology and pan-cancer analyses, we identified PPARG as a candidate shared target of DEHP and MEHP. PPARG was upregulated in HCC tissues, and higher expression was associated with poorer overall survival in the TCGA-LIHC cohort. Molecular docking and dynamics simulations predicted a more favorable and stable interaction between MEHP and PPARG than between DEHP and PPARG. In HepG2 cells, both compounds increased lipid accumulation and PPARG expression. Rosiglitazone promoted lipid accumulation and upregulated the lipid-storage genes DGAT2 and PLIN2, whereas GW9662 attenuated DEHP/MEHP-induced lipid accumulation and related transcriptional responses. Untargeted LC–MS metabolomics revealed relative alterations in phosphatidylcholine and phosphatidylethanolamine features and suggested perturbations in fatty acid-, bile acid-, arachidonic acid-, and nucleotide-related pathways. Collectively, these findings support a functional contribution of PPARG to DEHP/MEHP-associated lipid accumulation, potentially involving a DGAT2/PLIN2-related lipid-storage program, and provide mechanistic clues to phthalate-associated metabolic dysregulation in liver cancer cells. Download: Download high-res image (364KB) Download: Download full-size image
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Cell Death & Disease
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2023
·Vol. 14
·期 1
·1-12
·
IF 9
Yuan Baoshi,Shi Kexin,Zha Juanmin,Cai Yujia,Gu Yue,Huang Kai,Yue Wenchang,Zhai Qiaocheng,Ding Ning,Ren Wenyan,He Weiqi,Xu Ying,Wang Tao
Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Chemoresistance leads to poor responses to conventional therapy in patients with osteosarcoma. The discovery of novel effective therapeutic targets and drugs is still the main focus of osteosarcoma research. Nuclear receptors (NRs) have shown substantial promise as novel therapeutic targets for various cancers. In the present study, we performed a drug screen using 29 chemicals that specifically target 17 NRs in several different human osteosarcoma and osteoblast cell lines. The retinoic acid receptor beta (RARb) antagonist LE135, peroxisome proliferator activated receptor gamma (PPARg) antagonist T0070907, liver X receptor (LXR) agonist T0901317 and Rev-Erba agonist SR9011 significantly inhibited the proliferation of malignant osteosarcoma cells (U2OS, HOS-MNNG and Saos-2 cells) but did not inhibit the growth of normal osteoblasts. The effects of these NR modulators on osteosarcoma cells occurred in a dose-dependent manner and were not observed in NR-knockout osteosarcoma cells. These NR modulators also significantly inhibited osteosarcoma growth in vivo and enhanced the antitumour effect of doxorubicin (DOX). Transcriptomic and immunoblotting results showed that these NR modulators may inhibit the growth of osteosarcoma cells by regulating the PI3K/AKT/mTOR and ERK/mTOR pathways. DDIT4, which blocks mTOR activation, was identified as one of the common downstream target genes of these NRs. DDIT4 knockout significantly attenuated the inhibitory effects of these NR modulators on osteosarcoma cell growth. Together, our results revealed that modulators of RARb, PPARg, LXRs and Rev-Erba inhibit osteosarcoma growth both in vitro and in vivo through the mTOR signaling pathway, suggesting that treatment with these NR modulators is a novel potential therapeutic strategy.
研究领域:
肿瘤学
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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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PubMed
高影响因子
ACS Applied Materials & Interfaces
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2024
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IF 8.3
Nian-Yuan Xu,Jun Li,Mei-Ling Wang,Xue-Yu Chen,Ruizhi Tang,Xi-Qiu Liu
The current research models of breast cancer are usually limited in their capacity to recapitulate the tumor microenvironment in vitro. The lack of an extracellular matrix (ECM) oversimplifies cell–cell or cell–ECM cross-talks. Moreover, the lack of tumor-associated macrophages (TAMs), that can comprise up to 50% of some solid neoplasms, poses a major problem for recognizing various hallmarks of cancer. To address these concerns, a type of direct breast cancer cells (BCCs)–TAMs coculture organoid model was well developed by a sequential culture method in this study. Alginate cryogels were fabricated with appropriate physical and mechanical properties to serve as an alternative ECM. Then, our previous experience was leveraged to polarize TAMs inside of the cryogels for creating an in vitro immune microenvironment. The direct coculture significantly enhanced BCCs organoid growth and cancer aggressive phenotypes, including the stemness, migration, ECM remodeling, and cytokine secretion. Furthermore, transcriptomic analysis and protein–protein interaction networks implied certain pathways (PI3K-Akt pathway, MAPK signaling pathway, etc.) and targets (TNF, PPARG, TLR2, etc.) during breast cancer progression in a TAM-leading immune microenvironment. Future studies to advance treatment strategies for BCC patients may benefit from using this facile model to reveal and target the interactions between cancer signaling and the immune microenvironment.
研究领域:
肿瘤学
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生物医学工程
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细胞生物学
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免疫学
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组织工程
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PubMed
高影响因子
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