Marine Drugs
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2021
·Vol. 19
·期 9
·485
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IF 5.118
Ying Yan,Zhoumin Niu,Boyang Wang,Shangge Zhao,Chao Sun,Yuting Wu,Yuying Li,Hao Ying,Hongbing Liu
Dysregulation of cholesterol homeostasis is a major risk factor of atherosclerosis, which can lead to serious health problems, including heart attack and stroke. Liver X receptor (LXR) α and β are transcription factors belonging to the nuclear receptor superfamily, which play important roles in cholesterol homeostasis. Selectively activating LXRβ provides a promising strategy for the treatment of atherosclerosis. Here, we employed atherosclerotic apoE-knockout mice to evaluate the effects of saringosterol, a phytosterol with potent and selective action for LXRβ, which we identified previously in edible marine seaweedSargassum fusiforme. We found that saringosterol treatment reduced the atherosclerotic plaque burden without having undesirable adverse hepatic effects in apoE-deficient mice fed an atherogenic diet. Meanwhile, reduced serum levels of cholesterol, accompanied by altered expression of LXR-regulated genes involved in cholesterol absorption, transport, efflux, excretion, and elimination, were observed in apoE-knockout mice after saringosterol treatment. Together, our study not only establishes saringosterol as an effective cholesterol-lowering and anti-atherogenic phytosterol but also provides insights into the underlying mechanism.Keywords:saringosterol;liver X receptor;cholesterol metabolism;atherosclerosis;Sargassum fusiforme
研究领域:
药理学
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心血管疾病
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海洋生物学
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DOI
PubMed
高影响因子
PHYTOCHEMISTRY
·
2023
·
IF 3.8
Qi Hong,Miao-Miao Guo,Jin Yang,Xing Wei,Li Liao,Xiu-Juan Xin,Di Zhang,Fa-Liang An
Four previously undescribed diketopiperazine-type alkaloids including one oxepin-containing diketopiperazine-type alkaloid, oxepinamide L (1), three 4-quinazolinone alkaloids, puniceloids E-G (10–12), together with 12 known analogues, protuboxepin D (2), oxepinamides D-G, J-K and I (3–9), puniceloids B-D (13–15) and protubonine B (16), were isolated from the culture of the marine-derived fungus Aspergillus puniceus FAHY0085. The structures of the previously undescribed compounds were comprehensively elucidated by detailed interpretation of their NMR and HRESIMS data. Their absolute configurations were unambiguously determined by ROESY experiments, Marfey's method, calculated ECD experiments and single-crystal X-ray diffraction analysis. Compounds (3–4, 6–8, 14–15) were evaluated for their cytotoxic activity against HepG2, MCF-7, SW1116 and HeLa cells and compound 6 and 14 showed moderate cytotoxic activity against HeLa cells with IC 50 49.61 ± 2.91 and 28.38 ± 1.57 μM, respectively. Compounds (1–8, 11–15) were screened for their transcriptional activation of liver X receptor α and compound 11 with known compounds 13–15 showed significant transcriptional activation of liver X receptor α with EC 50 values in the range 2–50 μM.
研究领域:
化学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
CHEMICAL & PHARMACEUTICAL BULLETIN
·
2015
·Vol. 63
·期 8
·628-635
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IF 1.164
Siyun Nian,Xia Gan,Xiangduan Tan,Zhenpeng Yu,Panfeng Wang,Xing Chen,Guoping Wang
Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) α/β were tested in vitro. Compound 26 had an IC50 value of 6.4 µM against LXRα and an IC50 value of 5.6 µM against LXRβ. Docking studies and the results of structure–activity relationships support the further development of this chemical series as LXRα/β antagonists.
研究领域:
药理学
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分子生物学
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DOI
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2020
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IF 6.551
Haifeng Zhang,Yingting Jia,Zhuoheng Tang,Lei Wang,Wenxin Hu,Junmin Gao,Jianying Hu,Min Yang
Wastewater reclamation and reuse is considered an attractive and practical method for coping with water scarcity . However, the presence of micropollutants in reclaimed water, including endocrine disrupting chemicals (EDCs), is a major public health concern. This study attempted to identify unknown EDCs with liver X receptor (LXRα) agonist/antagonist activities in reclaimed wastewater, using nuclear receptors binding extraction coupled with high-resolution mass spectrometry (NRBE-HRMS). In total, 105 compounds in the reclaimed wastewater exhibited LXRα-binding activity. Among them, two previously unknown LXRα-antagonist compounds, catechol and 4-acetamidoantipyrine, were identified, based on authentic standards. The two LXRα-antagonist compounds exhibited weak LXRα-antagonist activities in a yeast two-hybrid assay. Catechol and 4-acetamidoantipyrine inhibited the β-galactosidase activity induced by 60 nM of TO901317 in an LXRα yeast assay, with IC 20 values of 79,938.9 nM and 6286.4 nM, respectively. To the best of our knowledge, this is the first study to identify EDCs in reclaimed wastewater with LXRα-agonist/antagonist activity using the NRBE-HRMS method.
研究领域:
环境科学
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毒理学
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分析化学
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DOI
PubMed
高影响因子
ANESTHESIA AND ANALGESIA
·
2018
·Vol. 127
·期 3
·775
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IF 3.463
Gui Yulong,Li Aiyuan,Zhang Jie,Li Guan,Ruan Xia,Guo Qulian,Zou Wangyuan
BACKGROUND: Neuropathic pain is an intractable and complex disease. Recent studies have shown a close relationship between endoplasmic reticulum (ER) stress and neuropathic pain. Here, we investigated the effect of α-asarone, an ER stress inhibitor, on chronic constriction injury (CCI)–induced neuropathic pain. METHODS: Two parts were included in this study. In part 1, rats were assigned to 7 groups: the sham group, the sham + α-asarone 20 mg/kg group, the CCI group, the CCI + vehicle group, the CCI + α-asarone 5 mg/kg group, the CCI + α-asarone 10 mg/kg group, and the CCI + α-asarone 20 mg/kg group. After surgery, the rats were treated with α-asarone or normal saline daily. Pain thresholds were measured, and samples of the L3–6 spinal cord were taken for western blotting and immunofluorescence on day 7. In part 2, rats were intrathecally implanted with PE-10 tubes and divided into 4 groups: the CCI + α-asarone 20 mg/kg group, the CCI + α-asarone 20 mg/kg + vehicle group, the CCI + α-asarone 20 mg/kg + SR9243 group, and the CCI group. Five rats in each group were separated for behavioral tests 1 hour after intrathecal injection. The rest of them were killed for western blotting on day 7. RESULTS: In this study, CCI surgery significantly induced mechanical allodynia and thermal hyperalgesia. CCI surgery significantly induced activation of ER stress (PERK-eIF2α, IRE1α, CHOP, and XBP-1s) in rats. However, treatment with 20 mg/kg of α-asarone significantly alleviated CCI-induced activation of ER stress. Behavioral results showed that daily treatment with 20 mg/kg of α-asarone significantly alleviated CCI-induced nociceptive behaviors, on day 7 (mechanical allodynia, P = .016, 95% confidence interval, 0.645–5.811; thermal hyperalgesia, P = .012, 95% confidence interval, 0.860–6.507). Furthermore, α-asarone induced upregulated expression of liver X receptor β (LXRβ) and downstream proteins in the spinal cord. The LXR antagonist SR9243 completely inhibited the anti-ER stress and antinociceptive effects of α-asarone in rats. CONCLUSIONS: α-Asarone relieved CCI-induced neuropathic pain in an LXR-dependent manner. α-Asarone may be a potential agent for treatment of neuropathic pain.
研究领域:
神经科学
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药理学
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疼痛管理
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DOI
PubMed
高影响因子
BMC Complementary Medicine and Therapies
·
2023
·Vol. 23
·期 1
·1-14
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IF 3.9
Han Wenrun,Zhang Dandan,Zhang Peng,Tao Qianqian,Du Xiaoli,Yu Chunquan,Dong Pengzhi,Zhu Yan
IntroductionLiver X Receptor (LXR) agonists could attenuate the development of atherosclerosis but bring excess lipid accumulation in the liver. Danlou Recipe was believed to be a benefit for improving the lipid profile. Thus, it is unclear whether Danlou Recipe could attenuate hyperlipidemia without excess lipid accumulated in the liver of mice. This study aimed to clarify if Danlou Recipe could alleviate the progression of hyperlipidemia in mice without extra lipids accumulated in the liver.Methods Male murine macrophage RAW264.7 cells and murine peritoneal macrophages were used for the in vitro experiments. Cellular cholesterol efflux was determined using the fluorescent cholesterol labeling method. Those genes involved in lipid metabolism were evaluated by qRT‐PCR and western blotting respectively. In vivo, a mouse model of hyperlipidemia induced by P407 was used to figure out the effect of Danlou Recipe on reverse cholesterol transport (RCT) and hyperlipidemia. Ethanol extract of Danlou tablet (EEDL) was prepared by extracting the whole powder of Danlou Prescription from ethanol, and the chemical composition was analyzed by ultra-performance liquid chromatography (UPLC).Results EEDL inhibits the formation of RAW264.7 macrophage-derived foam cells, and promotes ABCA1/apoA1 conducted cholesterol efflux in RAW264.7 macrophages and mouse peritoneal macrophages. In the P407-induced hyperlipidemia mouse model, oral administration of EEDL can promote RCT in vivo and improve fatty liver induced by a high-fat diet. Consistent with the findings in vitro, EEDL promotes RCT by upregulating the LXR activities.Conclusion Our results demonstrate that EEDL has the potential for targeting RCT/LXR in the treatment of lipid metabolism disorders to be developed as a safe and effective therapy.
研究领域:
药理学
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心血管疾病
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脂质代谢
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2017
·
IF 2.896
Meijing Liu,Changhui Liu,Hao Chen,Xiaotao Huang,Xiaohui Zeng,Juncheng Zhou,Suiqing Mi
Schaftoside (SS) is a bioactive compound present in the Herba Desmodii Styracifolii (DS), a herb that has been used to treat cholelithiasis and urolithiasis in Chinese medicine. Whether SS inhibits cholesterol (Ch) gallstone formation has not been investigated. This study examined the effects of oral intake of SS on Ch gallstone formation in C57BL/6 mice fed a lithogenic diet. The rate of gallstone formation was recorded. Levels of Ch, triglycerides (TG) and bile salts (BS) were measured in the bile and serum. Liver histopathology was examined microscopically, and mRNA expression levels of key genes involved in cholesterol and bile metabolism were determined by qPCR . Mice fed SS were protected against gallstone formation, had increased biliary levels of BS, and reduced biliary Ch levels, resulting in a lower Ch saturation index (CSI). In addition, mice fed SS had lower serum TG and Ch levels, increased mRNA expression of liver X receptor α , ATP binding cassette transporter 5/8 (ABCG5/8), and ileal bile acid binding protein (IBABP) in the ileum, and of farnesoid X receptor and bile salt export protein (BSEP) in the liver and ileum. SS also protected against histologically determined liver damage. Overall, these data indicate that SS protects against Ch gallstone formation in mice, and that the effect is mediated by activation of ileal liver X receptor α and hepatic farnesoid X receptor.
研究领域:
药理学
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胃肠病学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
·
IF 3.322
Hengte Xing,Chuancai Liang,Chenyu Wang,Xiongfeng Xu,Yong Hu,Bo Qiu
In this study, we aim to investigate the effect of metformin on cholesterol synthesis and efflux-related genes in chondrocytes during osteoarthritis (OA) and explore the underlying mechanisms. Primary chondrocytes were harvested from Wistar rat cartilage and divided into control and treatment groups. Chondrocytes in the treatment group were treated with interleukin-1β (IL-1β) mimicking the inflammatory environment of osteoarthritis. Subsequently, RT-qPCR, Western blotting, immunofluorescence staining, and Cell Counting Kit-8 (CCK-8) were conducted. Significant reductions in phosphorylated AMP-activated protein kinase (p-AMPK) and silent information regulator 1 (SIRT1) protein expression were observed in both human OA chondrocytes and cultured primary murine chondrocytes treated with IL-1β, while AMP-activated protein kinase (AMPK) was not inhibited. Moreover, in the presence of IL-1β, metformin significantly increased the expression of p-AMPK and SIRT1 at the protein and mRNA level. Meanwhile, metformin could reverse IL-1β-induced cartilage extracellular matrix degradation in chondrocytes from the rat model of OA (treated by IL-β) by activating the AMPK/SIRT1 pathway. Moreover, metformin activated AMPK and SIRT1, mediated by the activation of SREBP-2 and HMGCR in OA chondrocytes. Inhibiting AMPK/SIRT1 activity by its specific inhibitor could suppress IL-1β-induced expression of LXRα, ABCA1 and ApoA1 and cholesterol efflux. Thus, metformin inhibits cholesterol synthesis and promotes cholesterol efflux by activating the AMPK/SIRT1 pathway in OA chondrocytes. This study improves our understanding of the effect of metformin on cholesterol accumulation in OA chondrocytes.
研究领域:
药理学
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风湿病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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