JOURNAL OF BIOMEDICAL SCIENCE
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2023
·Vol. 30
·期 1
·1-14
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IF 11
Shen Weiyi,Shao Wentao,Wang Qihan,Wang Bo,Zhao Gang,Gu Aihua,Jiang Zhaoyan,Hu Hai
Background Cholesterol gallstone disease is a common disease. Reducing cholesterol burden is important to prevent/treat gallstone. In this study, we investigated the application of diosgenin (DG) to prevent the formation of gallstone in mice.Methods Adult male C57BL/6J mice were fed with the lithogenic diet (LD) only or LD supplemented with DG or ezetimibe for 8 weeks. Incidences of gallstone formation were documented. Intestine and liver tissues were collected to measure the lipid contents and expression of genes in cholesterol metabolism. Caco2 cells were treated with DG to monitor the regulation on cholesterol absorption and the transcriptional regulation of Npc1l1 gene. Changes of gut microbiota by DG was analyzed. Intraperitoneal injection of LPS on mice was performed to verify its effects on STAT3 activation and Npc1l1 expression in the small intestine.Results LD led to 100% formation of gallstones in mice. In comparison, dietary DG or ezetimibe supplementary completely prevents gallstones formation. DG inhibited intestinal cholesterol absorption in mice as well as in Caco2 cells by down-regulation of Npc1l1 expression. DG could directly inhibit phosphorylation of STAT3 and its transcriptional regulation of Npc1l1 expression. Furthermore, DG could modulate gut microbiota profiles and LPS mediated STAT3 activation and Npc1l1 expression.Conclusion Our results demonstrated that dietary DG could inhibit intestinal cholesterol absorption through decreasing NPC1L1 expression to prevent cholesterol gallstone formation.
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
EMBO Molecular Medicine
·
2022
·Vol. 14
·期 2
·e14903
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IF 14.26
Zhe Zhang,Siyuan Qin,Yan Chen,Li Zhou,Mei Yang,Yongquan Tang,Jing Zuo,Jian Zhang,Atsushi Mizokami,Edouard C Nice,Hai-Ning Chen,Canhua Huang,Xiawei Wei
Entering a drug-tolerant persister (DTP) state of cancer cells is a transient self-adaptive mechanism by which a residual cell subpopulation accelerates tumor progression. Here, we identified the acquisition of a DTP phenotype in multidrug-resistant (MDR) cancer cells as a tolerance response to routine combination treatment. Characterization of MDR cancer cells with a DTP state by RNA-seq revealed that these cells partially prevented chemotherapy-triggered oxidative stress by promoting NPC1L1-regulated uptake of vitamin E. Treatment with the NPC1L1 inhibitor ezetimibe further enhanced the therapeutic effect of combinatorial therapy by inducing methuosis. Mechanistically, we demonstrated that NRF2 was involved in transcriptional regulation of NPC1L1 by binding to the −205 to −215 bp site on its promoter. Decreased DNA methylation was also related partially to this process. Furthermore, we confirmed that a triple-combination of chemotherapeutic agents, verapamil, and ezetimibe, had a significant anti-tumor effect and prevented tumor recurrence in mice. Together, our study provides a novel insight into the role of DTP state and emphasizes the importance of disrupting redox homeostasis during cancer therapy.
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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癌症治疗
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PubMed
高影响因子
FOOD CHEMISTRY
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2025
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IF 9.8
Yonglin Li,Shengmin Zhou,Jie Qiang,Yongsheng Cao,Guoyi Qu,Yuan Gao,Qi Li,Xiuzhu Yu
Butyrospermol, a minor yet important compound in camellia oil, has anti-inflammatory effects. However, its absorption, elimination, and the influence of oil on its bioavailability remain unclear. This study investigated the logP, stability in simulated digestive fluids and liver tissue, absorption parameters of different forms of butyrospermol, and binding of butyrospermol to the Niemann–Pick C1-like 1-N-terminal domain (NPC1L1-NTD). Results indicated that butyrospermol remained stable in the simulated gastric and intestinal fluids but underwent degradation in rat liver tissue. The bioavailability of the butyrospermol suspension was low owing to its poor water solubility. Unexpectedly, the bioavailability of butyrospermol in oil was also low. This was due to incomplete emulsification and the inhibitory effects of other triterpene alcohols in the oil, which prevented butyrospermol from binding to NPC1L1-NTD. Our study provides theoretical insights into the functional application of butyrospermol and calls for further investigations into its bioactivity and that of camellia oil.
研究领域:
食品科学
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药理学
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消化生理学
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PubMed
高影响因子
Advanced Healthcare Materials
·
2019
·Vol. 8
·期 8
·1800934
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IF 6.27
Yuan Liu,Dan Chen,Jialin Li,Dengning Xia,Miaorong Yu,Jinsong Tao,Xinxin Zhang,Li Li,Yong Gan
Gene vectors for oral delivery encounter harsh conditions throughout the gastrointestinal tract, and the continuous peristaltic activity can quickly remove the vectors, leading to inefficient intestinal permeation. Therefore, vectors have demanding property requirements, such as stability under various pH and, more importantly, efficient uptake in different intestinal segments. In this study, a functional polymer, cholesterol-grafted poly(β-amino ester) (poly[hexamethylene diacrylate-β-(5-amino-1-pentanol)] (CH-PHP)), is synthesized and electrostatically interacted with plasmid DNA to form a CH-PHP/DNA complex (CPNC). This complex is designed to target the Niemann–Pick C1-like receptor, a cholesterol receptor, to improve oral gene delivery efficacy. With the presence of cholesterol, CH-PHP shows mitigated cytotoxicity, enhanced enzyme resistance, and improved gene condensing ability. CPNC further contributes to ≈43.1- and 2.3-fold increases in luciferase expression in Caco-2 cells compared with PNC and Lipo 2000/DNA complexes, respectively. In addition, the in vivo transfection efficacy of CPNC is ≈4.1-, 2.1-, and 1.6-fold higher than that of Lipo 2000/DNA complexes in rat duodenum, jejunum, and ileum, respectively. Therefore, CPNC may be a promising delivery vector for gene delivery, and using a cholesterol-specific endocytic pathway can be a novel approach to achieve efficient oral gene transfection.
研究领域:
药剂学
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分子生物学
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DOI
PubMed
高影响因子
Marine Drugs
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2023
·Vol. 21
·期 12
·624
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IF 5.4
Zhuoqian He,Zhongyin Zhang,Pengfei Xu,Verena M. Dirsch,Limei Wang,KeWei Wang
Aberrantly high dietary cholesterol intake and intestinal cholesterol uptake lead to dyslipidemia, one of the risk factors for cardiovascular diseases (CVDs). Based on previous studies, laminarin, a polysaccharide found in brown algae, has hypolipidemic activity, but its underlying mechanism has not been elucidated. In this study, we investigated the effect of laminarin on intestinal cholesterol uptake in vitro, as well as the lipid and morphological parameters in an in vivo model of high-fat diet (HFD)-fed mice, and addressed the question of whether Niemann–Pick C1-like 1 protein (NPC1L1), a key transporter mediating dietary cholesterol uptake, is involved in the mechanistic action of laminarin. In in vitro studies, BODIPY-cholesterol-labeled Caco-2 cells were examined using confocal microscopy and a fluorescence reader. The results demonstrated that laminarin inhibited cholesterol uptake into Caco-2 cells in a concentration-dependent manner (EC50= 20.69 μM). In HFD-fed C57BL/6J mice, laminarin significantly reduced the serum levels of total cholesterol (TC), total triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C). It also decreased hepatic levels of TC, TG, and total bile acids (TBA) while promoting the excretion of fecal cholesterol. Furthermore, laminarin significantly reduced local villous damage in the jejunum of HFD mice. Mechanistic studies revealed that laminarin significantly downregulated NPC1L1 protein expression in the jejunum of HFD-fed mice. The SiRNA-mediated knockdown of NPC1L1 attenuated the laminarin-mediated inhibition of cholesterol uptake in Caco-2 cells. This study suggests that laminarin significantly improves dyslipidemia in HFD-fed mice, likely by reducing cholesterol uptake through a mechanism that involves the downregulation of NPC1L1 expression.Keywords:laminarin;high-fat diet;cholesterol uptake;NPC1L1
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高影响因子
FOOD CHEMISTRY
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2021
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IF 7.514
Zhuqing Dai,Jiangfeng Song,Ye Chen,Lei Feng,Yayuan Xu,Dajing Li,Caie Wu,Zhongyuan Zhang,Jun Liu
This study aims to develop novel lutein nanoparticles encapsulized by stevioside (LUT-STE, 165 ± 2 nm average particles size) and systematically evaluate its bioavailability. Multiple spectroscopy and NMR analyses showed lutein and stevioside could interact through hydrogen bonds, C H π interaction and van der Waals forces. Molecular docking simulation showed lutein was well distributed in the hydrophobic cavity of stevioside. Analyzed by Caco-2 cellular models, the transported amount of LUT-STE was 2.39 times that of lutein in 120 min with a P app (B → A)/ P app (A → B) value of 0.63 ± 0.04. Nystatin and dynasore significantly reduced the cellular uptake of LUT-STE by 41.3% and 57.7%, respectively. Compared with free lutein, LUT-STE increased the C max in mice plasma by 5.01-fold and promoted the accumulation in multiple organs. LUT-STE promoted the protein expressions of CD36, NPC1L1 and PPARγ in both cell and animal models. In conclusion, stevioside entrapment significantly promote the bioavailability of lutein through multiple transmembrane pathways.
研究领域:
药学
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营养学
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分子生物学
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药理学
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PubMed
高影响因子
Nature Communications
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2026
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IF 18.1
He Peiyi,Zhang Jibin,Xu Mingheng,Liu Beilan,Lai Keren,Miao Guifeng,Zhao Xiaoxi,Wang Xinyue,Tan Guozhu,Wang Xiaorui
Transcytosis-mediated delivery effectively enhances tumor penetration of nanodrugs but is less efficacious in stroma-rich tumors. Cancer associated fibroblasts (CAF) can represent a physical barrier for drug delivery in tumor cells. Herein, by selectively targeting NPC1L1-cancer associated fibroblasts, surface-displayed cholesterol enhances the delivery of a platinum nanodrug (PtD-Chol) in stroma-rich tumors, restoring anti-tumor efficacy. The findings reveal that PtD-Chol, acting through the ‘shared entry portal’ of NPC1L1 triggers cross-multicellular transport (CMCT) within tumors, shuttling PtD-Chol across the CAF barrier via the endocytic recycling compartment-endoplasmic reticulum-Golgi pathway, thereby enabling deep penetration into tumor. This strategy restores nanodrug efficacy in CAF-rich refractory tumor models in female mice, and suppresses both primary growth and CAF-driven metastasis via tumor microenvironment remodeling. This proposed nanodrug delivery paradigm offers an approach to tackle the critical barriers of tumor penetration and therapeutic efficacy in nanomedicine.
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高影响因子
PHYTOMEDICINE
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2023
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IF 7.9
Chao Meng,Lingye Zhou,Lin Huang,Qi Gu,Xinyue Du,Cheng Wang,Fanglan Liu,Chunhua Xia
Background Hypercholesterolemia is widely implicated in the etiology of coronary heart disease , stroke, and dementia. Evidence suggests that chlorogenic acid (CA) reduces the risk of cardiovascular disease. Purpose The current study aims to explore the underlying molecular mechanism of CA in lowering cholesterol based on pregnane X receptor (PXR) and sterol regulatory element-binding protein 2 (SREBP2) regulatory pathways and their interactions with heat shock protein 90 (HSP90). Methods A hypercholesterolemic mouse model, HepG2 and Caco2 cell models, metabolomics analysis, and co-immunoprecipitation (COIP) were used to study the mechanism of CA lowering cholesterol. Results Treatment of the hypercholesterolemic mice with CA for 12 weeks significantly reduced body weight, blood lipid, hepatic lipid accumulation , and increased lipid excretion. The nuclear aggregation of PXR and SREBP2 was inhibited simultaneously. In addition, the expression of downstream target genes, including Niemann-pick C1-like 1 (NPC1L1) and 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR), was downregulated after CA administration. Furthermore, in HepG2 and Caco2 cell models, CA reduced intracellular cholesterol levels by inhibiting the nuclear translocation of PXR and SREBP2 and the expression of NPC1L1 and HMGCR. SREBP2 interacts with PXR through HSP90, and CA reduces the binding stability of SREBP2 and HSP90 and enhances the binding of PXR and HSP90, thus reducing the nuclear accumulation of SREBP2 and PXR simultaneously. Moreover, CA promoted the phosphorylation of AMP-activated protein kinase (AMPK) and its binding to SREBP2. This was not conducive to the binding of HSP90 and SREBP2 but enhanced the binding of HSP90 and PXR, thereby inhibiting the nuclear translocation of SREBP2 and PXR and reducing intracellular cholesterol levels. However, no noticeable direct binding between AMPK and PXR was observed. Conclusion CA downregulates NPC1L1 and HMGCR expression by acting on the AMPK/SREBP2 direct pathway and the AMPK/SREBP2/HSP90/PXR indirect pathway, thus retaining cholesterol homeostasis.
研究领域:
药理学
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分子生物学
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心血管疾病
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代谢组学
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PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2023
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IF 3.4
Zhiquan Wang,Zhe Wang,Miao Lin,Bowen Zheng,Jinlan Zhang
Hyperlipidemia is a global metabolic disorder characterized by dysregulation of lipid metabolism. This dysregulation is closely associated with the altered homeostasis of cholesterol-cholesteryl ester (CE) metabolism in systemic circulation , and some organs. Additionally, the relationship between oxidized cholesteryl ester (oxCE) and the disease has also gained attention. Currently, there is a lack of comprehensive research on the alterations in cholesterol-CE metabolism in the context of hyperlipidemia, as well as the characteristics of lipid-lowering agents in regulating this metabolic state. Therefore, 40 oxCEs were identified in the hamster liver sample, and novel ultrahigh performance liquid chromatography−tandem mass spectrometry (UHPLC-MS/MS) methods were established for simultaneous analysis of cholesterol, 57 CEs, and 40 oxCEs in the serum, liver, adipose tissue, and intestine of hyperlipidemic hamsters. This study investigated the metabolic alterations between cholesterol-CE/oxCE in hyperlipidemic hamsters and those treated with lipid-lowering agents, including the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe and the acyl coenzyme A : cholesterol acyltransferase (ACAT) inhibitor avasimibe . The study findings demonstrate metabolic disorders in cholesterol-CE/oxCE homeostasis in hyperlipidemic hamsters. Lipid-lowering agent therapy can improve the metabolic dysregulation caused by hyperlipidemia, with distinct characteristics: ezetimibe is more effective in reducing cholesterol, while avasimibe is more effective in reducing CEs/oxCEs. Eight potential biomarkers indicating the dysregulation of cholesterol-CE metabolism caused by hyperlipidemia and its improvement by lipid-lowering agents have been identified in the serum. This study offers new insights into the hyperlipidemia pathophysiology and the mechanisms of lipid-lowering agents from a novel perspective on cholesterol-CE/oxCE metabolic homeostasis.
研究领域:
代谢学
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药理学
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脂质组学
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生物化学
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PubMed
高影响因子
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