CyTA-Journal of Food
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2024
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IF 2
Fang Luo,WenLuer Meng,Ruo-Shi Hao,Xiangxuan Yang,Jinbo Yang,Ye-Wei Huang,Jun Sheng,Xuanjun Wang
This study investigated the impact of Oleanolic Acid (OA) on cholesterol metabolism and. MTT assays demonstrated that OA had no cytotoxic effects on HepG2 cells at concentrations below 20 μM. Subsequent experiments focused on 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), a key enzyme in cholesterol biosynthesis. OA significantly reduced HMGCR protein expression without affecting other enzymes. Further investigations revealed that OA reduced the protein and mRNA expression of HMGCR and its upstream regulator Sterol regulatory element binding protein-2 (SREBP-2) in HepG2 cells. OA activated Adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK), enhancing HMGCR phosphorylation and inhibiting its activity. Molecular docking experiments suggested that OA could suppress HMGCR enzymatic activity through hydrophobic interactions, reducing catalytic efficiency. Overall, OA downregulated HMGCR expression and activity, leading to decreased cholesterol synthesis. These findings highlight OA’s regulatory role in cholesterol metabolism and its potential for improving atherosclerosis (AS), supporting its application in functional food development.
研究领域:
药理学
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生物化学
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分子生物学
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细胞生物学
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营养学
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DOI
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Xuan Jiang,Manli Wang,Guoliang Cui,Yuanyuan Wu,Zhonghong Wei,Suyun Yu,Aiyun Wang,Wei Zou,Yanhong Pan,Xiaoman Li,Yin Lu
Background Tetramethylpyrazine (TMP), a key bioactive constituent derived from Ligusticum wallichii Franchat , has demonstrated efficacy in mitigating multidrug resistance (MDR) in human breast cancer (BC) cells. However, the precise mechanisms underlying its action remain poorly understood. Purpose Cancer stem cells (CSCs) are widely recognized as the primary contributors to MDR. This investigation seeks to elucidate the role and mechanisms through which TMP counteracts MDR by attenuating CSC-like characteristics. Methods Various assays, including flow cytometry, sphere formation, and Western blotting, were employed to evaluate TMP's effects on breast cancer stem cell (BCSC)-like phenotypes in vitro. In vivo , extreme limiting dilution assays and immunohistochemistry (IHC) were executed to assess the impacts of TMP on BCSC frequency and the levels of stemness markers. Mechanistically, RNA sequencing was performed to uncover the key biological processes involved in TMP's effects on BCSCs. Further experiments, encompassing micro scale thermophoresis (MST), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and amino acid mutation analyses, were utilized to identify the essential targets and corresponding binding sites of TMP. Finally, the effects of TMP on BCSC-like phenotypes were confirmed using cells with mutated amino acid residues, which allowed us to investigate the specificity of TMP's binding sites. To further evaluate the impact of TMP on drug resistance, doxorubicin-resistant MCF7 (MCF-7 ADR ) cells, along with corresponding cell lines harboring mutated amino acid residues, were employed. Results TMP was found to inhibit BCSC-like properties both in vitro and in vivo , evidenced by a reduction in the CD44 + /CD24 - population, sphere formation capability, and expression of stemness markers. Mechanistic studies revealed that TMP targets 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol biosynthesis. TMP binds to Asp-767 of HMGCR, thereby inhibiting its activity and reducing cholesterol synthesis. The influence of TMP on BCSC-like phenotypes was nullified by overexpression of wild-type HMGCR, while mutations in the binding site of HMGCR had no effect on TMP's inhibition of BCSC-like properties. Additionally, TMP mitigated MDR by targeting HMGCR. Conclusion These findings suggest that TMP alleviates MDR by reducing BCSC-like traits through targeting HMGCR and disruption of cholesterol biosynthesis in BC. This provides new insights into the mechanisms through which TMP alleviates MDR and offers new lead compound for exploring HMCGR antagonists.
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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细胞生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2026
·Vol. 63
·期 1
·772
·
IF 5.5
Tian Xiaofeng,Liu Qing,Zhang Jiacheng,Du Huijiao,Wei Zhaoran,Sun Linjie,Gao Jiamin,Zhao Ruiting,Wang Lei,Zhang Yizhou
In recent years, the association between abnormal cholesterol metabolism and Parkinson’s disease (PD) has attracted considerable attention, but the specific mechanism remains controversial. First, we used Mendelian Randomization (MR) analysis to clarify the relationship between cholesterol and PD. Subsequently, scRNA-seq and RNA-seq were used to identify the crucial role of astrocyte 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) in this process. Moreover, we verified its downstream target genes by RNA-seq, in vivo and in vitro experiments. The upstream transcriptional regulator of HMGCR was identified by database and validated by luciferase reporter and siRNA knockdown assays. The results of the MR analysis showed that low cholesterol levels may increase the risk of PD. This phenomenon was also observed in the PD mouse model. The scRNA-seq and RNA-seq results showed that astrocyte HMGCR played an important role in PD. Increasing astrocytic HMGCR alleviated cholesterol level and PD-related phenotypes. Mechanistically, astrocytic HMGCR-mediated cholesterol alleviated PD phenotypes by inhibiting Nuclear Factor Kappa-B (NF-κB) neuroinflammation. Furthermore, knocking down Forkhead Box O1 (FOXO1) restored HMGCR expression and cholesterol levels, subsequently inhibiting NF-κB activation. Our research indicated that the cholesterol synthesis disorder in astrocytes driven by HMGCR can exacerbate the pathogenesis of PD by promoting neuroinflammation. Targeting HMGCR in astrocytes will be a potential therapeutic approach.
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2023
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IF 8.2
Chunhua Zhu,Mingjing Mou,Leilei Yang,Zedong Jiang,Mingjing Zheng,Zhipeng Li,Tao Hong,Hui Ni,Qingbiao Li,Yuanfan Yang,Yanbing Zhu
κ-Carrageenase can degrade κ-carrageenan to produce bioactive κ-carrageenan oligosaccharides (KCOs) that have potential applications in pharmaceutical, food, agricultural, and cosmetics industries. Immobilized enzymes gain their popularity due to their good reusability, enhanced stability, and tunability. In this study, the previously characterized catalytic domain of Pseudoalteromonas purpurea κ-carrageenase was covalently immobilized on the synthesized amine-modified zeolitic imidazolate framework-8 nanoparticles with the formation of cross-linked enzyme aggregates, and the immobilized κ-carrageenase was further characterized. The immobilized κ-carrageenase demonstrated excellent pH stability and good reusability, and exhibited higher optimal reaction temperature, better thermostability, and extended storage stability compared with the free enzyme. The KCOs produced by the immobilized κ-carrageenase could significantly decrease the TC, TG, and LDL-C levels in HepG2 cells, increase the HDL-C level in HepG2 cells, and reduce the free fatty acids level in Caco-2 cells. Biochemical assays showed that the KCOs could activate AMPK activity, increase the ratios of p-AMPK/AMPK and p-ACC/ACC, and downregulate the expression of the lipid metabolism related proteins including SREBP1 and HMGCR in the hyperlipidemic HepG2 cells. This study provides a novel and effective method for immobilization of κ-carrageenase, and the KCOs produced by the immobilized enzyme could be a potential therapeutic agent to prevent hyperlipidemia.
研究领域:
生物化学
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药学
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生物技术
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·1-12
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IF 3.9
Liao Xuemei,Cheng Xin,Zhuang Ruirong,Zhou Beidou
The total synthesis of compound 1 , a chiral diglyceride metabolite present in both humans and fungi, was achieved via a seven-step route, affording the target molecule in 2.33% overall yield. The synthetic strategy involved: (1) selective protection of the terminal hydroxyl group of chiral ketal 2 with a sterically hindered benzyl group, followed by ketal deprotection to yield benzyl ether 4 ; (2) protection of the terminal hydroxyl group of benzyl ether 4 with a bulky silyl protecting group, and subsequent esterification of the remaining hydroxyl with erucic acid to generate ester 6 ; (3) removal of the silyl protecting group from ester 6 , followed by esterification of the liberated hydroxyl group with pentadecanoic acid to afford ester 8 ; and (4) selective deprotection of the benzyl group of ester 8 to furnish compound 1 . Network pharmacology and molecular docking studies identified 196 potential targets of compound 1 , with AKT1, ALB, CASP3, EGFR, HSP90AA1, IGF1, and SRC highlighted as potential hub targets. In silico analysis suggested potential therapeutic applications in diabetes, neuro-systemic diseases, thyroid hormone disorders, lipid disorders, tumors, and gynaecological diseases. Furthermore, in silico screening using three databases identified 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) as a potential biological target. However, in vitro HMGCR inhibition assays failed to demonstrate a significant reduction in cholesterol levels in human blood upon treatment with compound 1 . These findings contribute to the understanding of the chemical synthesis and biological activity of chiral diglycerides and provide a basis for future research in this area.
研究领域:
有机化学
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药物化学
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药理学
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生物化学
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计算生物学
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代谢性疾病
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癌症研究
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DOI
PubMed
高影响因子
Journal of Functional Foods
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2019
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IF 3.197
Sen Li,Wenwen Yu,Xiao Guan,Kai Huang,Jing Liu,Dandan Liu,Ruiqian Duan
To evaluate the hypolipidemic effects of millet, we investigated the function of millet ethanol extract and whole grain millet on lipid metabolism by in vitro and in vivo models in this study. Results showed that millet ethanol extract significantly decreased lipid accumulation, total cholesterol and triglyceride levels in cells. Millet supplementation dramatically decreased total cholesterol levels, altered lipid profiles, and down-regulated the expression of genes SREBP-1C, FAS, HMGCR that related to hepatic lipid metabolism in rat fed with high fat diet (HFD). In addition, we also examined the level of short-chain fatty acids (SCFAs) and the composition of gut microbiota in rats. SCFAs including acetate, propionate and butyrate were increased in millet supplemented HFD rat cecum. High dose millet supplementation decreased the population of Firmicutes and increased Actinobacteria. In conclusion, our findings suggested that millet may exhibit hypolipidemic effect by regulating lipid metabolism related genes expression or gut microbiota composition.
研究领域:
营养学
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微生物学
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分子生物学
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产品关联
DOI
高影响因子
PHYTOMEDICINE
·
2023
·
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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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Jingyi Ren,Jinshi Zuo,Bowen Yin,Dan Huang,Rui Wen,Huanting Pei,Jiarui Liu,Yadong Zhang,Siqi Zhu,Shuman Zhen,Yuxia Ma
Perfluorooctanesulfonate (PFOS) is a widespread, persistent environmental pollutant that exerts apparent liver toxicity. Flaxseed oil (FO), a dietary oil rich in α-linolenic acid, has been demonstrated to possess a diverse array of health benefits. However, whether FO protects against PFOS-induced liver injury and its underlying mechanisms remain unclear. C57/BL6 mice were orally treated with different concentrations of FO alone or in combination with 10 mg/kg of PFOS for 28 consecutive days. Blood and liver tissues were collected for proteomic, histopathological, biochemical, immunohistochemical, and molecular examinations. Results demonstrated that FO supplementation reduced PFOS-induced liver injury, as evidenced by a decrease in histopathological changes, serum transaminase (ALT and AST) levels, levels of oxidative stress, and inflammatory cytokine (TNF-α, IL-1β, and IL-6) levels. Proteomic analyses showed that differentially expressed proteins were enriched in cholesterol metabolic pathways when comparing the PFOS group to the FO supplementation groups. The expression of cholesterol metabolism-related proteins was also subsequently measured, revealing that FO supplementation decreased the protein expressions of SREBP2, HMGCR, and LDLR while increasing the expression of CYP7A1. This study demonstrates that FO can alleviate PFOS-induced hepatotoxicity by regulating hepatic cholesterol metabolism, indicating that FO may serve as an effective dietary intervention for preventing liver injury caused by PFOS.
研究领域:
毒理学
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营养学
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分子生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL AND MOLECULAR MEDICINE
·
2025
·
IF 12.9
Zhu Lijun,Tang Zhaohui,Jiang Wen,Dong Yuwen,Li Xiaofei,Huang Kai,Wu Tiancong,Xu Lingyan,Guo Wenjie,Gu Yanhong
Radiotherapy-induced DNA damage can lead to apoptotic cell death and trigger an anti-tumor immune response via the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway, which senses cytoplasmic double-stranded DNA. However, radiotherapy resistance poses a significant challenge in treating cancers, including colorectal cancer (CRC). Understanding the mechanisms underlying this resistance is crucial for developing effective therapies. Here we report that radiotherapy enhances cholesterol synthesis, which subsequently inhibits the cGAS–STING pathway, leading to radiotherapy resistance. Mechanistically, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) levels increase rapidly in response to radiation, resulting in increased cholesterol synthesis. This increased cholesterol sequesters STING in the endoplasmic reticulum, hindering its activation and downstream interferon signaling. Elevated HMGCR and cholesterol levels correlate with poor prognosis and reduced response to radiation therapy in patients with CRC. Importantly, pharmacological inactivation of HMGCR significantly enhanced radiotherapy responsiveness in animal models, dependent on cGAS–STING signaling-mediated anti-tumor responses. Our findings reveal that radiotherapy-induced cholesterol inhibits cGAS–STING signaling, facilitating tumor immune escape. Therefore, combining statins with radiotherapy represents a promising therapeutic strategy for treating CRC.
研究领域:
肿瘤学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2021
·
IF 6.244
Hu Zengchun,Cheng Chuandong,Wang Yue,Chen Tianrui,Tu Junhong,Niu Chaoshi,Xing Rong,Wang Yang,Xu Yinghui
Neuroblastoma is the most common extracranial neuroendocrine tumor in childhood. Although many studies have tried to find effective treatments, there are still numerous limitations in current clinical targeted therapy. So, it is important to find new therapeutic targets and strategies from a new perspective. Our previous study reported that the androgen receptor (AR) promotes the growth of neuroblastoma in vitro and in vivo. Based on documentary investigation, we postulated that the AR–SCAP–SREBPs-CYP17/HMGCR axis may regulate cholesterol and androgens synthesis and form a positive enhancement loop promoting NB progression. Clinical samples and Oncomine database analysis proved the activation of AR–SCAP–SREBPs-CYP17/HMGCR axis in neuroblastoma. The combination of inhibitors of HMGCR (statins) and CYP17A1 (abiraterone acetate) showed synergistic effect that significantly inhibited the proliferation and migration with decreased expression of related genes detected in vitro and in vivo suggesting the dual-targeted therapy had the potential to inhibit the progression of neuroblastoma in spite of its MYCN status. This study provides new ideas for clinical treatment of neuroblastoma with efficacy and reduced toxicity.
研究领域:
肿瘤学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 20
·7049
·
IF 4.6
Yanan Li,Pingping Dong,Long Dai,Shaoping Wang
The active peptide (APE) ofEupolyphaga sinensisWalker, which is prepared by bioenzymatic digestion, has significant antihyperlipidemic effects in vivo, but its mechanism of action on hyperlipidemia is not clear. Recent studies on amino acid metabolism suggested a possible link between it and hyperlipidemia. In this study, we first characterized the composition of APE using various methods. Then, the therapeutic effects of APE on hyperlipidemic rats were evaluated, including lipid levels, the inflammatory response, and oxidative stress. Finally, the metabolism-regulating mechanisms of APE on hyperlipidemic rats were analyzed using untargeted and targeted metabolomic approaches. The results showed that APE significantly reduced the accumulation of fat, oxidative stress levels, and serum pro-inflammatory cytokine levels. Untargeted metabolomic analysis showed that the mechanism of the hypolipidemic effect of APE was mainly related to tryptophan metabolism, phenylalanine metabolism, arginine biosynthesis, and purine metabolism. Amino-acid-targeted metabolomic analysis showed that significant differences in the levels of eight amino acids occurred after APE treatment. Among them, the expression of tryptophan, alanine, glutamate, threonine, valine, and phenylalanine was upregulated, and that of arginine and proline was downregulated in APE-treated rats. In addition, APE significantly downregulated the mRNA expression of SREBP-1, SREBP-2, and HMGCR. Taking these points together, we hypothesize that APE ameliorates hyperlipidemia by modulating amino acid metabolism in the metabolome of the serum and feces, mediating the SREBP/HMGCR signaling pathway, and reducing oxidative stress and inflammation levels.Keywords:active peptide (APE) ofEupolyphaga sinensisWalker;hyperlipidemic;untargeted and targeted metabolomics;amino acid metabolism
研究领域:
代谢组学
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药理学
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生物化学
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营养科学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
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IF 5.988
Jie Du,Xiaodong Chen,Yongshun Zhao,Tingting Zhao,Dalong Wang,Zujia Chen,Changyuan Wang,Qiang Meng,Jialin Yao,Huijun Sun,Kexin Liu,Jingjing Wu
CYP46A1 is a brain-specific enzyme responsible for cholesterol homeostasis. Inhibition of CYP46A1 activity serves as a therapeutic target for excitatory neurotoxicity. Sesame is a common medicine and food resource; its component lignans possess various pharmacological activities. In this study, the inhibitory effects of sesame lignans on CYP46A1 activity were investigated. Inhibition kinetics analyses revealed that sesamin and sesamolin produce mixed partial competitive inhibition of CYP46A1, while sesamol produces non-competitive inhibition. Notably, molecular simulations revealed that the sesame lignans have excellent orientations within the active cavity of CYP46A1. Importantly, the sesame lignans had high permeability coefficients and low efflux ratios. Furthermore, sesamin significantly reduced the levels of 24S-hydroxycholesterol in rat plasma and brain tissues, and down-regulated the protein expressions of CYP46A1, NMDAR2A, NMDAR2B, and HMGCR. Collectively, sesame lignans exhibit significant inhibitory effects on CYP46A1 activity, highlighting their potential therapeutic role in treating excitatory neurotoxicity.
研究领域:
药理学
·
神经科学
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生物化学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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