Chinese Journal of Natural Medicines
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2024
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IF 4
Wenhui YAO,Rongpin TAO,Kai WANG,Xuansheng DING
ABSTRACT Icariin, a flavonoid glycoside, is extracted from Epimedium . This study aimed to investigate the vascular protective effects of icariin in type 1 diabetic rats by inhibiting high-mobility group box 1 (HMGB1)-related inflammation and exploring its potential mechanisms. The impact of icariin on vascular dysfunction was assessed in streptozotocin (STZ)-induced diabetic rats through vascular reactivity studies. Western blotting and immunofluorescence assays were performed to measure the expressions of target proteins. The release of HMGB1 and pro-inflammation cytokines were measured by enzyme-linked immunosorbent assay (ELISA). The results revealed that icariin administration enhanced acetylcholine-induced vasodilation in the aortas of diabetic rats. It also notably reduced the release of pro-inflammatory cytokines, including interleukin-8 (IL-8), IL-6, IL-1β, and tumor necrosis factor-alpha (TNF-α) in diabetic rats and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs). The results also unveiled that the pro-inflammatory cytokines in the culture medium of HUVECs could be increased by rHMGB1. The increased release of HMGB1 and upregulated expressions of HMGB1-related inflammatory factors, including advanced glycation end products (RAGE), Toll-like receptor 4 (TLR4), and phosphorylated p65 (p-p65) in diabetic rats and HG-induced HUVECs, were remarkably suppressed by icariin. Notably, HMGB1 translocation from the nucleus to the cytoplasm in HUVECs under HG was inhibited by icariin. Meanwhile, icariin could activate G protein-coupled estrogen receptor (GPER) and sirt1. To explore the role of GPER and Sirt1 in the inhibitory effect of icariin on HMGB1 release and HMGB-induced inflammation, GPER inhibitor and Sirt1 inhibitor were used in this study. These inhibitors diminished the effects of icariin on HMGB1 release and HMGB1-induced inflammation. Specifically, the GPER inhibitor also negated the activation of Sirt1 by icariin. These findings suggest that icariin activates GPER and increases the expression of Sirt1, which in turn reduces HMGB1 translocation and release, thereby improving vascular endothelial function in type 1 diabetic rats by inhibiting inflammation.
研究领域:
药理学
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内分泌学
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心血管疾病
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分子生物学
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DOI
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
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2026
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IF 4.8
Zhanji Li,Jingyao Wei,Hanqian Ye,Yanhong Zheng,Haimei Yang,Chen Su,Lujian Mo,Tinghao Jiang,Chunke Nong,Zhongsheng Yi
Halogenated bisphenols (HBPs) are widely detected environmental contaminants present in water systems, soil, and biota. The incorporation of halogen substituents (Cl, Br) enhances their environmental persistence and potential toxicological effects. Understanding the cellular responses to HBPs exposure in living organisms is therefore essential for evaluating their human health implications. This study comprehensively characterizes the binding patterns and interaction mechanisms of HBPs with the G protein-coupled estrogen receptor (GPER) through an integrated approach combining multispectral analysis, molecular dynamics (MD) simulations, and quantum chemical calculations. Computational results reveal that hydrogen bonding and van der Waals interactions primarily mediate GPER-HBPs binding, with binding affinity modulated by both halogen atom count and the chemical nature of bridging groups between benzene rings. Binding of HBPs induces significant structural alterations in GPER, including conformational rearrangements, molecular compaction, enhanced hydrophobicity, and modifications to the microenvironment and secondary structure. Fourier-transform infrared (FT-IR) and three-dimensional fluorescence spectroscopy confirm secondary structure reorganization, particularly evidenced by reduced β-sheet content. Stern-Volmer analysis establishes static quenching as the dominant mechanism, correlated with specific HBPs binding modes and sites. Density functional theory (DFT) calculations identify hydrogen bonds, halogen bonds, and electrostatic interactions as key driving forces, supplemented by weaker intermolecular contributions. These insights advance the assessment of health risks associated with HBPs-type environmental pollutants.
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PubMed
高影响因子
AQUATIC TOXICOLOGY
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2017
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IF 4.129
Jiebo Lin,Caihong Wang,Jinfeng Liu,Randy A. Dahlgren,Weiming Ai,Aibing Zeng,Xuedong Wang,Huili Wang
Triclosan (TCS) exposure has widely adverse biological effects such as influencing biological reproduction and endocrine disorders. While some studies have addressed TCS-induced expression changes of miRNAs and their related down-stream target genes, no data are available concerning how TCS impairs miRNA expression leading us to study up-stream regulating mechanisms. Four miRNAs (miR-125b, miR-205, miR-142a and miR-203a) showed differential expression between TCS-exposure treatments and the control group; their functions mainly involved fatty acid synthesis and metabolism. TCS exposure led to the up-regulation of mature miR-125b that was concomitant with consistent changes in pri-mir-125b-1 and pri-mir-125b-3 among its 3 pri-mir-125bs. Up-regulation of miR-125b originated from direct shear processes involving the two up-regulated precursors, but not pri-mir-125b2. Increased expression of pri-mir-125b-1 and pri-mir-125b-3 resulted from nfe2l2- and c/ebpα-integration with positive control elements of promoters for the two precursors. The overexpression of transcriptional factors, nfe2l2 and c/ebpα, initiated the promoter activity for the miR-125b precursor. CpG islands and Nfe2l2 were involved in constitutive expression of mir-125b-1 and mir-125b-3 . The activities of two promoter regions, −487 to −1 bp for pri-mir-125b1 and −1327 to +14 bp for pri-mir-125b-3 having binding sites for NFE2 and Nfe2l2/MAF:NFE2, were higher than other regions, further demonstrating that the transcriptional factor Nfe2l2 was involved in the regulation of pri-mir-125b1 and pri-mir-125b-3. TCS’s estrogen activity resulted from its effects on GPER, a novel membrane receptor, rather than the classical ERα and ERβ. These results explain, to some extent, the up-stream mechanism for miR-125b up-regulation, and also provide a guidance to future mechanistic study on TCS-exposure.
研究领域:
毒理学
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分子生物学
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环境科学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2026
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IF 5.2
Ze-Pei Zhao,Shi-Ye Zhu,Ying-Huang Hu,Yu-Ke Wan,Shang-Jun Xu,Jie-Zhi Ma,Deng-Ni Lai,An-Wei Chen,Yuan Yang,Lin Luo,Lin-Ying Cao
Benzotriazole ultraviolet stabilizers (BUVSs) are ubiquitous emerging contaminants with documented multifaceted toxicity. However, their potential impacts on human placental development and underlying mechanisms remain poorly understood. This study investigated the effects of three representative BUVSs (UV-P, UV-326, and UV-328) on trophoblast function via G-protein-coupled estrogen receptor (GPER) pathway. Molecular dynamics simulations revealed that UV-328 binds to GPER with higher affinity than UV-P and UV-326, which even exceeds that of the native ligand 17β-estradiol (E2). Calcium influx assays demonstrated that all three BUVSs activated GPER signaling pathway in a concentration-dependent manner, with lowest observed effect concentrations (LOECs) of 10–100 nM. Each BUVS enhanced trophoblast proliferation—most potently by UV-328 (LOEC = 1 nM)—through GPER-mediated upregulation of Cyclin D1 and Ki-67, indicating promotion of cell cycle progression. Wound-healing and transwell assays showed that all three BUVSs promoted trophoblast migration and invasion with LOECs of 1–100 nM via GPER pathway. Furthermore, the three BUVSs opposing regulated expression between epithelial (down) and mesenchymal (up) markers and upregulated the expression of matrix metalloproteinases (MMP2/9) through activating GPER, indicating that GPER-mediated epithelial–mesenchymal transition and extracellular matrix remodeling should be key events in BUVSs-induced migration and invasion. UV-328 consistently exhibited the strongest effects on trophoblast functions, aligning with its superior GPER activation potency. Importantly, the LOECs for UV-328–induced trophoblast dysfunction fall within nanomolar ranges relevant to estimated human exposure levels. Together, these results reveal GPER-mediated mechanistic pathways through which BUVSs disrupt trophoblast function and highlight their potential risk in gestational disorders.
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
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2026
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IF 4.9
Haimei Yang,Chen Su,Lujian Mo,Yanhong Zheng,Hanqian Ye,Zetong Song,Jingyao Wei,Yuan Sun,Haimei Huang,Zhongsheng Yi
An integrated approach combining multispectral techniques and multiscale simulations systematically reveals PAE–GPER interactions from molecular details to conformational changes. • The results show that substituent chain length and spatial distribution jointly regulate binding modes and significantly influence complex stability and protein conformational dynamics. • The established structure–interaction relationships provide a theoretical basis for endocrine risk assessment of PAEs and the rational design of safer alternatives. The G protein-coupled estrogen receptor (GPER) orchestrates numerous physiological processes, yet the structural determinants governing its interaction with ubiquitous endocrine-disrupting phthalate esters (PAEs) remain poorly defined. Here, we integrated multispectral characterization with computational modeling to elucidate the PAE–GPER interaction landscape. Virtual screening of 23 PAE congeners established that binding affinity was critically modulated by alkyl chain length, with molecular docking implicating Glu-275 and Gln-138 as essential anchoring residues. Molecular dynamics simulations revealed the formation of stable complexes, evidenced by a reduced radius of gyration (Rg) indicative of protein compaction, while solvent-accessible surface area (SASA) and root-mean-square fluctuation (RMSF) analyses demonstrated compound-specific remodeling of the protein microenvironment—findings corroborated by three-dimensional fluorescence spectroscopy. Thermodynamic profiling, MM-PBSA free energy calculations, and reduced density gradient (RDG) analyses converged to show that binding was spontaneous and predominantly mediated by van der Waals interactions and hydrophobic effects, with hydrogen bonding constituting a central stabilizing interaction. Steady-state fluorescence confirmed a static quenching mechanism, and Förster resonance energy transfer (FRET) analysis yielded donor–acceptor distances of 2.65–3.31 nm, situating these interactions within the optimal energy-transfer regime (0.5 R₀ –1.5 R₀ ). Molecular electrostatic potential (MEP) mapping further highlighted synergistic hydrophobic and electrostatic contributions to recognition. Finally, Fourier-transform infrared (FT-IR) spectroscopy detected ligand-induced secondary-structure rearrangements, exemplified by a 3.03% increase in β-sheet content upon dibutyl phthalate (DBP) binding. Collectively, these data identify steric constraints and hydrophobic complementarity as pivotal determinants of PAE–GPER engagement, providing a mechanistic framework for evaluating the endocrine-disrupting potential of structurally diverse environmental contaminants. Download: Download high-res image (325KB) Download: Download full-size image
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高影响因子
Biomolecules & Therapeutics
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2023
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IF 3.7
Nayun Kim,Junhye Kwon,Ui Sup Shin,Joohee Jung
Colorectal cancer (CRC) is one of the most high-risk cancers; however, it has been suggested that estrogen signaling in CRC could have a protective effect. Therefore, we focused on the function of the G protein-coupled estrogen receptor (GPER) among the estrogen receptors in CRC. In this study, we investigated the therapeutic effect of resveratrol via GPER in CRC (RKO and WiDr) cells, CRC cell-derived xenograft models, and organoids (30T and 33T). Resveratrol significantly suppressed cell viability and proliferation in highly GPER-expressing RKO cells compared to that in low GPER-expressing WiDr cells. In xenograft models, resveratrol also delayed tumor growth and exhibited a high survival rate depending on GPER expression in RKO-derived tumors. Furthermore, resveratrol significantly inhibited the viability of organoids with high GPER expression. Additionally, the anticancer effect of resveratrol on CRC showed that resveratrol rapidly responded to GPER, while increasing the expression of p-ERK and Bax and cleaving PARP proteins.
研究领域:
肿瘤学
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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
SCIENCE OF THE TOTAL ENVIRONMENT
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2024
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IF 8.2
Ting-Ting He,Xin Li,Jie-Zhi Ma,Yuan Yang,Shiye Zhu,Jianhua Zeng,Lin Luo,Yu-Long Yin,Lin-Ying Cao
Triclocarban (TCC) and triclosan (TCS) have been detected ubiquitously in human body and evoked increasing concerns. This study aimed to reveal the induction risks of TCC and TCS on triple negative breast cancer through non-genomic GPER-mediated signaling pathways. Molecular simulation indicated that TCC exhibited higher GPER binding affinity than TCS theoretically. Calcium mobilization assay displayed that TCC/TCS activated GPER signaling pathway with the lowest observed effective concentrations (LOEC) of 10 nM/100 nM. TCC and TCS also upregulated MMP-2/9, EGFR, MAPK3 but downregulated MAPK8 via GPER-mediated signaling pathway. Proliferation assay showed that TCC/TCS induced 4 T1 breast cancer cells proliferation with the LOEC of 100 nM/1000 nM. Wound-healing and transwell assays showed that TCC/TCS promoted 4 T1 cells migration in a concentration-dependent manner with the LOEC of 10 nM. The effects of TCC on breast cancer cells proliferation and migration were stronger than TCS and both were regulated by GPER. TCC/TCS induced migratory effects were more significantly than proliferative effect. Mechanism study showed that TCC/TCS downregulated the expression of epithelial marker (E-cadherin) but upregulated mesenchymal markers (snail and N-cadherin), which was reversed by GPER inhibitor G15. These biomarkers results indicated that TCC/TCS-induced 4 T1 cells migration was a classic epithelial to mesenchymal transition mechanism regulated by GPER signaling pathway. Orthotopic tumor model verified that TCC promoted breast cancer in-situ tumor growth and distal tissue metastasis via GPER-mediated signaling pathway at human-exposure level of 10 mg/kg/d. TCC-induced tissue metastasis of breast cancer was more significantly than in-situ tumor growth. Overall, we demonstrated for the first time that TCC/TCS could activate the GPER signaling pathways to induce breast cancer progression.
研究领域:
肿瘤学
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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
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2020
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IF 4.872
Wenhao Huang,Weiming Ai,Weiwei Lin,Fang Fang,Xuedong Wang,Haishan Huang,Randy A. Dahlgren,Huili Wang
Herein, eight common endocrine disrupting chemicals (EDCs) were exposed to zebrafish ( Danio rerio ) to investigate the relationship between different EDCs and their activated estrogen receptors. Under acute exposure, we identified five major malformation types whose incidence and deformity modes differed among EDCs. Luciferase analysis divided the EDC receptors into four categories: (i) triclosan (TCS), 17ß-estradiol (E2) and estriol (E3) mainly activated GPER expression; (ii) bisphenol A (BPA), p -(tert-octyl) phenol (POP), 17α-ethynylestradiol (EE2), E2 and E3 activated ERβ expression; (iii) E2 and E3 acted on both GPER and ERβ; and (iv) estrone (E1) and 9,9-bis(4-hydroxyphenyl)fluorene (BHPF) had little effect on the two receptors. In vivo immunofluorescence experiments on 96-hpf larvae provided evidence that TCS and POP acted on GPER and ERβ, respectively, while E2 acted on the two receptors simultaneously. Luciferase activities in the promoter regions of gper (−986 to −488) and erβ (−1998 to −1496) were higher than those in other regions, identifying these key regions as targets for transcription activity. TCS promoted GPER expression by acting on the JUND transcription factor, while POP promoted ERβ expression by activating the Foxl1 transcription factor. In contrast, E2 mainly regulated transcription of GPER and ERβ by Arid3a. These findings provide compelling evidence that different EDCs possess varying estrogen receptors, leading to differential regulatory pathways and abnormality symptoms. These results offer an experimental strategy and fundamental information to assess the molecular mechanisms of EDC-induced estrogen effects.
研究领域:
毒理学
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环境科学
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分子生物学
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发育生物学
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DOI
PubMed
高影响因子
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