BRAIN RESEARCH BULLETIN
·
2024
·
IF 3.5
Yu Bi,Ziyi Xie,Xiang Cao,Huanyu Ni,Shengnan Xia,Xinyu Bao,Qinyue Huang,Yun Xu,Qingxiu Zhang
Microglia-associated neuroinflammation plays essential roles in pathology of acute stroke. Cedrol, a natural compound extracted from ginger, has been shown to confer inhibitory effects on inflammation in various diseases. However, whether Cedrol suppresses neuroinflammation and protects brains from acute ischemic injury still remains unclear. In this study, we found that Cedrol inhibited microglia activation and the production of inflammatory factors in LPS-challenged microglia and the penumbra region of middle cerebral artery occlusion (MCAO) mice. We also found that Cedrol reduced the infarct size and mNSS scores and improved acute cerebral ischemia-induced behavioral outcomes, suggesting remarked neuroprotection of Cedrol. Molecular docking analysis showed that Cedrol bound to estrogen receptor β (ERβ) with moderate-strong affinity. Intriguingly, treatment with fulvestrant, an ER blocker, abolished the anti-inflammatory effects of Cedrol. Cedrol significantly reversed the LPS- and MCAO-induced increases in phosphorylation levels of IκB and NF-κB P65 in primary microglia and MCAO mice, respectively. Additionally, Cedrol was observed to rescue LPS-induced shuttling of NF-κB P65 from cytoplasm to nuclei in primary microglia, indicating inhibitory effects of Cedrol on NF-κB signaling. These results suggest microglia associated neuroinflammation may be mediated by ERβ-NF-κB signaling pathway. Together, our study reveals that Cedrol protected brain function from acute cerebral ischemia through inhibition of microglia-associated neuroinflammation via ERβ-NF-κB signaling pathways, and Cedrol may serve as an alternative option for treatment of acute stroke injury.
研究领域:
神经科学
·
药理学
·
分子生物学
·
炎症
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Jieli Pan,Jinjun Ji,Xingpan Xin,Yihong Gan,Zixin Huang,Jing Chen,Ying Li,Jie Bao,Yujun Tang,Chengping Wen,Li Xu
Background Systemic lupus erythematosus (SLE) is an autoimmune disease with marked female predominance. Lupus nephritis (LN), one of its most severe manifestations, is strongly associated with aberrant activation of signal transducer and activator of transcription 3 (STAT3). Estrogen receptor β (ERβ) has been reported to exert immunoregulatory effects, but its role in restraining STAT3 signaling in LN remains unclear. Purpose This study aimed to investigate whether genistein, a phytoestrogen with selective affinity for ERβ, can modulate the ERβ–STAT3 axis to attenuate lupus nephritis. Methods The therapeutic effects of genistein were evaluated in MRL/lpr and pristane-induced lupus mouse models and in LPS-stimulated macrophages. Macrophage polarization, oxidative stress, mitochondrial function, and ERβ–STAT3 signaling were assessed using flow cytometry, biochemical assays, immunoblotting, and bioinformatic analyses. Results Genistein significantly ameliorated renal injury, reduced proteinuria, and decreased serum autoantibody and IL-6 levels in lupus models. Mechanistically, genistein suppressed M1 macrophage polarization by activating ERβ and inhibiting STAT3 and NF-κB signaling. Genistein also attenuated oxidative stress by preserving mitochondrial membrane potential, reducing reactive oxygen species production, and restoring antioxidant capacity. Pharmacological blockade of ERβ markedly attenuated the anti-inflammatory effects of genistein, confirming ERβ-dependent regulation of STAT3 signaling. Conclusion This study identifies ERβ as a negative regulator of STAT3-driven inflammation and demonstrates that genistein therapeutically engages this axis to suppress macrophage-mediated renal injury, offering a promising therapeutic strategy for lupus nephritis.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2021
·
IF 4.013
Yuanyuan Wu,Mengnan Zeng,Ruiqi Xu,Beibei Zhang,Shengchao Wang,Benke Li,Yuxuan Kan,Bing Cao,Xiaoke Zheng,Weisheng Feng
Background Melanoma is an aggressive cancer with a rapidly increasing incidence rate worldwide. Acteoside has been shown to have antitumor effects in multiple human cancers; however, the underlying function and mechanisms of acteoside in melanoma remain unclear. Purpose This study explored the inhibitory effect of acteoside on melanoma and the possible mechanisms. Methods Acteoside (15 mg/kg, 30 mg/kg) was administered to mice daily for 21 days. ICI182,780 (0.5 mg/kg) was intraperitoneally injected 30 min before acteoside administration three times a week to evaluate whether the effects elicited by acteoside were mediated via the estrogen receptor . Tumor growth and metabolism, cardiac function, ROS and apoptosis levels in the spleen, serum inflammatory factors, and immune cells in the spleen were monitored. STAT3 , p-STAT3, CD31 , and survivin levels in tumor tissues were measured via immunofluorescence. Ras, Raf1, STAT3, p-STAT3, Bcl-2, Bax, cleaved caspase-3, and cleaved caspase-9 levels in tumor tissues were determined via Western Blotting . Results The results showed that acteoside inhibited melanoma growth, alleviated inflammation levels in mice, attenuated ROS and apoptosis levels in the spleen, downregulated the levels of CD31, survivin, Ras, Raf1, p-STAT3, and Bcl-2, and upregulated the levels of ER β , Bax, cleaved caspase-3, and cleaved caspase-9. Moreover, the effect of acteoside was blocked by ICI182,780. Conclusion Acteoside may promote the apoptosis of tumor cells by regulating the ER β -Ras/Raf1-STAT3 signaling axis, thus inhibiting the occurrence and development of melanoma.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
免疫学
✓ 已验证
DOI
PubMed
高影响因子
NEUROIMMUNOMODULATION
·
2021
·Vol. 29
·期 1
·63-69
·
IF 2.492
Liu Hong,Zhong Lili,Dai Qiaomei,Yang Jing,Zhang Yuwei,Zhang Bo,Jiang Ying
Introduction: Alzheimer’s disease is the most popular neurodegenerative disorder with no effective drugs to stop the progression. Zuoguiwan (ZGW), a traditional Chinese herbal medicine, has been applied in many diseases. Our study aimed to detect the function and mechanisms of ZGW in Alzheimer’s disease (AD). Methods: The rat models of AD were established by streptozotocin (STZ), and the function of ZGW on cognitive dysfunction was measured with the Morris water maze test. The concentration of pro-inflammatory mediators was accessed by enzyme-linked immunosorbent assay. The relative mRNA expression of ERβ was detected by real-time quantitative PCR. Results: The treatment with ZGW could suppress the cognitive impairment by the findings of escape latency and time spent in the target quadrant and the increased concentration of IL-1β, IL-6, and TNF-α induced by STZ. STZ might repress the mRNA levels of ERβ, and ZGW management weakened the declined mRNA expression of ERβ. ZGW might play a protective role in AD rats against the injury of STZ on cognition and neuro-inflammation by improving the mRNA expression of ERβ. Conclusion: The results indicated that ZGW might be a novel therapeutic strategy to slow the process of AD by modulating ERβ
研究领域:
神经科学
·
药理学
·
中医
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2025
·Vol. 40
·期 1
·e70270
·
IF 1.7
Yawen Li,Yishan Li,Kunping Yang,Wanjie Liu,Ming Yang,Shuo Wang,Wei Feng,Guangfu Lv,Jiaming Sun
To screen for anti-PMO active components in Cornus officinalis based on ERβ enzyme activity using affinity ultrafiltration and molecular docking techniques.ERβ enzyme and UHPLC-Q-Exactive Orbitrap MS were employed to analyze the anti-PMO activity and predict the components of different concentrations of ethanol extracts of C. officinalis . Molecular docking was used to verify the interaction mechanism between small molecule ligands and ERβ. The anti-PMO activity of the predicted components was further verified using MC3T3-L1 cells. The results showed that the ERβ enzyme can serve as a target enzyme for screening anti-PMO components. The 50% ethanol extract exhibited the best activity. UHPLC-Q-Exactive Orbitrap MS identified and analyzed 17 potential active components. Based on the binding rate and molecular docking results, the following three active components were identified: sweroside, 4-hydroxycinnamic acid, and cornuside. In vitro activity validation confirmed that these components have potential anti-PMO effects. The ERβ enzyme can be used as a potential target enzyme for screening anti-PMO active components in traditional Chinese medicine. The combination of affinity ultrafiltration and molecular docking provides an effective and rapid method for active component screening, offering valuable references for the targeted therapy, mechanism exploration, and quality control of traditional Chinese medicine.
研究领域:
生药学
·
天然产物化学
·
分子生物学
·
中医药学
·
药物发现
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Lei Wu,Wenqing Cheng,Haoke Xiang,Yaping Zhu,Yiran Jiang,Zixuan Wei,Mengqi Shao,Liyuan Tian,Yan Sun,Chao Lu
Chaihu Shugan San produces rapid antidepressant-like effects within 2 h in female CRS-exposed mice. • The rapid effect is comparable in onset to ketamine in female chronically stressed mice. • Hippocampal TC2N is a negative regulator of the rapid antidepressant-like action of CSS. • TC2N down-regulation is associated with hippocampal ERβ–eNOS–CaMKII–BDNF signaling. • The estrogen receptor β-linked mechanism was demonstrated in female mice and requires validation in males. Ethnopharmacological relevance Chaihu Shugan San (CSS), a classical seven-herb formula from the Ming-dynasty text Jing-Yue Quanshu, is widely prescribed for depressive disorders in China. Previous preclinical studies reported antidepressant-like effects only after weeks of repeated administration, mostly in male animals. Whether a single dose of CSS can produce rapid antidepressant-like effects in female animals, and through what mechanism, remains unclear. Aim of the study To determine whether a single administration of CSS produces rapid antidepressant-like effects in female mice exposed to chronic restraint stress (CRS), and to explore the underlying hippocampal mechanism. Methods and materials CSS quality was controlled by HPLC quantification of four index components. Female CRS mice received a single dose of CSS (1, 2 or 4 g/kg, i. g.) or ketamine (10 mg/kg, i. p.), followed by behavioral testing (tail suspension, forced swimming, sucrose preference and open field tests) within 2–24 h. Hippocampal RNA sequencing, RT-qPCR, Western blotting and ELISA were used to identify and validate candidate targets; hippocampal AAV-mediated TC2N overexpression and pretreatment with the ERβ antagonist acolbifene or the CaMKII inhibitor KN-93 were used for interventional validation. Results Batch-to-batch variation of the four index components was below 10% (RSDs 3.51–5.66%), with naringin (313.07 ± 11.16 μg/mL) and hesperidin (196.40 ± 11.11 μg/mL) as the major constituents. Acute administration of CSS (2 and 4 g/kg), like ketamine, shortened immobility time in the tail suspension test at 2 h and in the forced swimming test at 12 h, and restored sucrose preference at 24 h, without affecting locomotor activity. Hippocampal transcriptomics identified Tc2n as up-regulated by CRS and down-regulated by CSS, with Esr2, Nos3 and Camk2a showing the opposite pattern; these changes were confirmed at the mRNA and protein levels within 2 h. Hippocampal TC2N overexpression or pretreatment with acolbifene or KN-93 abolished the rapid behavioral effects of CSS and the associated changes in ERβ–eNOS–CaMKII–BDNF signaling. Conclusion CSS produces rapid, ketamine-comparable antidepressant-like behavioral effects in female CRS-exposed mice, accompanied by down-regulation of hippocampal TC2N and involvement of ERβ, eNOS, CaMKII and BDNF. Because only female mice were studied, these findings are specific to females and support an estrogen-linked mechanism that warrants confirmation in male animals and further translational study. Download: Download high-res image (318KB) Download: Download full-size image
✓ 已验证
DOI
高影响因子
ChemMedChem
·
2016
·Vol. 12
·期 3
·235-249
·
IF 2.98
Silong Zhang,Zhiyong Wang,Zhiye Hu,Changhao Li,Chu Tang,Kathryn E. Carlson,Junjie Luo,Chune Dong,John A. Katzenellenbogen,Jian Huang,Hai-Bing Zhou
Graphical Add a new element ! This is the first report of selenophene-core compounds as estrogen receptor (ER) ligands. In transcription assays, several selenophenes were profiled as superagonists for ERα; moreover, a few selenophenes exhibited antiproliferative activity similar to that of 4-hydroxytamoxifen in MCF-7 breast cancer cells while being nontoxic toward normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the ER. The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for the estrogen receptor (ER) has been well recognized. In this study we expanded the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure–activity relationship (SAR) analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene core and the nature of these substituents having a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene ( 2 f ) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most selenophenes were found to exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene ( 2 b ), bis(4-fluoro-3-hydroxyphenyl)3-bromoselenophene ( 6 f ), and 2,3,5-tris(hydroxyphenyl)thiophenes ( 8 b and 8 d ) profiling as superagonists for ERα; however, several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8 c showing antiproliferative effects similar to that of 4-hydroxytamoxifen in breast cancer MCF-7 cells while being nontoxic to normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the estrogen receptor.
研究领域:
药理学
·
化学
·
癌症研究
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Chao Lu,Lingang Zhao,Liyuan Tian,Chenguang Lin,Lei Wu
Ethnopharmacological relevancy Chaihushugan san (CSS), a classic formula for soothing the liver and relieving depression, has been identified to produce rapid antidepressant-like effects in female mice. However, the gender predominance and underlying mechanisms of CSS's antidepressant remain unclear. Aim of the study In this study, we focused on unraveling the gender predominance of CSS in antidepressant and the specific neuronal mechanisms that mediate this predominance. Methods and materials Tail suspension test (TST), forced swimming test (FST) and sucrose preference test (SPT) were used to evaluate depressive phenotypes or antidepressant-like effects of CSS in female and male chronic unpredictable mild stress (CUMS) mice model. RNA-sequencing was used to screen specific target for CSS antidepressant gender dominance. RT-PCR and elisa were used to detect the expressions of specific molecule, hormones, and inflammatory factors in the hippocampus. hippocampal viral overactivation and pharmacological blockade were used to detect the correlation between CSS antidepressant gender dominance and related targets. Results In the present study, both female and male mice displayed depressive phenotypes including significant increasing immobility time in TST and reducing sucrose preference ratio in SPT after exposing CUMS for 3 weeks. However, acute administration of CSS (2, 4 g/kg) improved the depressive phenotypes only in female mice or not male mice at 2 h later. Moreover, the expressions of TC2N were increased only in female mice after exposing CUMS for 3 weeks, which were also reversed by CSS after a single administration 2 h later, but no alterations in male mice. The hippocampal expressions of estrogen receptor β (Erβ), pro-inflammatory factors (IL-1β and TNF-α) and anti-inflammatory factors (IL-10, TGF-β and IL-1Rα) were all abnormal in female CUMS mice model, which were all normalized by CSS. Furthermore, overactivation of hippocampal TC2N by AAV-TC2N +/+ blocked the antidepressant-like effects of CSS and the up-regulation of hippocampal Erβ in female mice. However, inhibition of Erβ blunted the antidepressant-like effects of CSS and CSS's suppression of pro-inflammatory factors (IL-1β and TNF-α), which had no any effect on hippocampal TC2N and anti-inflammatory factors (IL-10 and TGF-β). Conclusions The study revealed that CSS had antidepressant superiority in female mice depending on inhibiting hippocampal TC2N and then activating Erβ, further inhibiting the release of pro-inflammatory factors to produce antidepressant effects, which provided a basis for the guidance of CSS in clinical application, new ideas and targets for the development of drugs for depression with gender differences.
研究领域:
民族药理学
·
神经科学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2020
·
IF 9.038
Naima Hamid,Muhammad Junaid,Rakia Manzoor,Pan-Pan Jia,De-Sheng Pei
Phthalate esters (PAEs) pose prominent ecological risks owing to their multiplex toxicity potentials and ubiquitous detection in the environment. Therefore, this study aims to prioritize the individual and mixtures of six PAEs based on their toxicological implications using in vitro and vivo models exposed at environmentally relevant concentrations. Results were further confirmed using in silico Combination index (CI) and Independent action (IA), and molecular docking models. Among PAEs, DEHP revealed prominent in vitro/vivo toxicity followed by DEP, DBP, and DMP. Importantly, binary mixtures particularly C2-C6 and C11-C15 exhibited greater developmental toxicity, apoptosis, and perturbed the HPG pathway. The CI and IA models forecasted antagonistic and additive effects at Fa = 0.5 and Fa = 0.9 using in vitro Acinetobacter sp. Tox2. Conversely, in zebrafish, the IA model predicted mixture effects in the following order: additive > synergistic > antagonistic on the regulation of the HPG pathway, which was consistent with experimental results from Acridine Orange (AO) staining and apoptosis gene expression. Molecular docking for estrogen receptors (ERα, ERβ) revealed the highest binding energy scores for DEHP, compared to other PAEs. In short, our findings confirm that individual and mixtures of PAEs behave as xenoestrogens in the freshwater ecosystem with DEHP as a priority compound.
研究领域:
环境毒理学
·
计算生物学
·
分子生物学
·
水生生态学
✓ 已验证
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2020
·
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
·
环境科学
·
分子生物学
·
发育生物学
✓ 已验证
DOI
PubMed
高影响因子
Nano Today
·
2024
·
IF 13.2
Ziyao Chen,Dongju Zhao,Meng Cheng,Fan Yang,Yining Liu,Jin Chang,Yan Dou
Alzheimer's disease (AD) has much higher incidence and mortality in women, largely attributed to the dramatic decline in estrogen levels during menopause. Therefore, tailoring therapeutic strategies targeting estrogen deprivation is essential to achieve female-specific AD treatment. Herein, we developed a multifunctional phytoestrogen nanomodulator (LQ-LPs) and revealed its feasibility and key pharmacological mechanisms for female-sensitive AD management. Benefiting from the greatly improved bioavailability and pharmacokinetics by liposomes , LQ-LPs amplified multiple biological properties of loaded liquiritigenin against estrogen-deprived AD progression, including enhancing synaptoprotective and anti-apoptotic effects through activation of ERβ/BDNF/ERK signaling, as well as simultaneously inhibiting Ca 2+ influx spike, oxidative damage , and cholinergic dysfunction caused by glutamate excitotoxicity . Taking advantage of the favorable brain-targeting properties conferred by intranasal delivery, LQ-LP administration exhibited remarkable anti-AD efficacy in reversing ovariectomy-induced neuropathology and rescuing cognitive deficits in estrogen-deprived AD mice. This work reveals for the first time the attractive promise of phytoestrogen-derived versatile nanotherapeutics for female-specific AD management, providing advanced insights into precision drug development for female AD.
研究领域:
药理学
·
纳米技术
·
神经科学
·
老年医学
·
女性健康研究
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）