Animals
·
2024
·Vol. 14
·期 6
·961
·
IF 2.7
Lei Xie,Ziyi Niu,Shimin Xiao,Hongyuan Wang,Yongpu Zhang
Simple SummaryThe ingestion of excessive nitrate can affect the thyroid gland and cause thyroid dysfunction in humans. In the present study, amphibian embryos were exposed to nitrate, thyroxine and methimazole (a thyroid peroxidase inhibitor) during embryonic development to further explore the effects of nitrate on the thyroid. The results showed that nitrate, thyroxine and methimazole inhibited embryo growth and development. Additionally, methimazole and high concentrations of nitrate downregulated the genes related to thyroid morphogenesis and cholesterol metabolism, while upregulating the genes related to inflammation and apoptosis. These suggested that nitrate not only damaged the thyroid gland, but also affected the formation of the thyroid, thus affecting embryonic development.AbstractIn recent years, nitrate (NO3-N) pollution in water bodies has been increasing due to the excessive use of nitrogen-based fertilizers. Exposure to NO3-N during the development of amphibian embryos may have lasting effects on the growth and development of individuals and even threaten their survival, but the toxicity mechanism of NO3-N in amphibian embryos prior to thyroid morphogenesis remains unclear. In the present study,Bufo gargarizanswas selected as the model organism to investigate the toxic effects of 10 mg/L and 100 mg/L NO3-N exposure (N10 and N100) on amphibian embryos using methimazole (MMI) and exogenous thyroxine (T4) as the reference groups. We found that T4, MMI, N10 and N100 inhibitedB. gargarizansembryo growth and development, with MMI and N100 showing the earliest and strongest effects. Transcriptome analysis revealed that MMI and NO3-N (especially N100) significantly downregulated genes related to thyroid morphogenesis and cholesterol metabolism, while upregulating genes related to inflammation and apoptosis. Together, these results contribute to a deeper understanding of the complex mechanisms by which NO3-N disruptsB. gargarizansembryonic development, reveal the potential risks of NO3-N pollution to other aquatic organisms, and provide insights into the conservation of a broader ecosystem.
研究领域:
生态毒理学
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分子生物学
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PubMed
高影响因子
MACROMOLECULAR BIOSCIENCE
·
2020
·Vol. 20
·期 7
·1900438
·
IF 3.416
Ting Bai,Bobo Zhu,Dongyan Shao,Ziyang Lian,Pei Liu,Junling Shi,Jie Kong
Targeting the distinct cholesterol metabolism of tumor cells is proposed as a novel way to treat tumors. Blocking acyl-CoA cholesterol acyltransferase-1 (ACAT-1) by the inhibitor avasimible (Ava), which elevates intracellular free cholesterol levels, is shown to effectively induce apoptosis. However, Ava faces disadvantages of poor water solubility, a short half-life, and no capability for fluorescence detection, which have greatly limited its application. Herein, a fluorescent hyperstar polymer (FHSP) is developed to encapsulate Ava to improve its ability to inhibit HeLa cells and K562 cells. The results of this study show that the obtained Ava–FHSP micelles possess a high drug loading capacity of 22.7% and bright green fluorescence. Ava and Ava–FHSP are cytotoxic to both HeLa and K562 cells and cause reductions in cell size, nuclear lysis, and chromatin condensation and hindered proliferation of both cell types by causing S phase cell cycle arrest. Further mechanistic analysis indicates that Ava–FHSP reduces the protein and messenger RNA expression of ACAT-1 and significantly increases intracellular free cholesterol levels, which can increase endoplasmic reticulum stress and finally cause cell apoptosis. All these results suggest that this fluorescent hyperstar polymer represents a potential therapeutic tumor strategy by changing the cholesterol metabolism of tumor cells.
研究领域:
生物化学
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肿瘤学
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药物递送系统
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PubMed
高影响因子
BMC CANCER
·
2025
·Vol. 25
·期 1
·1-16
·
IF 3.4
Zhang Mingxiang,Yang Tao,Qian Youcun
Background Dysregulated fatty acid metabolism is a key contributor to poor prognosis in glioma, and targeting cholesterol metabolism represents a promising therapeutic strategy. Apolipoprotein L4 (APOL4), a member of the Apolipoprotein L family, has been implicated in lipid metabolism, but its role in glioma remains unclear. Methods RNA-sequencing were performed to analysis gene expression under exogenous cholesterol treatment. Comprehensive bioinformatics analyses were performed using CGGA datasets to evaluate APOL4 expression, clinical correlations, and prognostic significance in GBM. In vitro experiments, including CRISPR-Cas9 mediated APOL4 knockdown, MTT assays, wound healing assays and immunofluorescence were performed to validate the oncogenic role of APOL4. Xenograft mouse models were employed to validate tumor growth in vivo. Results RNA-sequencing showed that exogenous cholesterol upregulated the expression of APOL4 in U-87 cells. Clinical database analysis revealed that APOL4 was significantly upregulated in human glioblastoma. Genetic depletion of APOL4 markedly suppressed glioblastoma cell proliferation in vitro and impaired xenograft tumor growth in vivo. Furthermore, APOL4 localized to late endosomes and lysosomes, where it likely facilitated the cytoplasmic transport of exogenous cholesterol, supporting tumor cell growth. Conclusions Our study identifies APOL4 as a novel regulator of cholesterol trafficking in glioma cells, promoting glioblastoma progression. These findings highlight APOL4 as a potential therapeutic target for glioma treatment.
研究领域:
肿瘤学
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分子生物学
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医学
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DOI
PubMed
高影响因子
Journal of Functional Foods
·
2016
·
IF 3.973
Chun-Feng Guo,Di Zhao,Ya-Hong Yuan,Tian-Li Yue,Bin Liu,Jing-Yan Li
The hypocholesterolaemic effects of milk fermented by Lactobacillus casei F0822 with bile salt hydrolase activity were investigated in hamsters fed a cholesterol-rich diet. Fermented milk (FM) exhibited dose-dependent hypocholesterolaemic activity. Sterilized and low-dose FM did not significantly affect the lipid profile of hamsters, whereas high-dose FM significantly reduced the levels of serum total cholesterol (TC) and non-high-density lipoprotein cholesterol (non-HDL-C), as well as hepatic TC and esterified cholesterol (EC). The daily faecal total bile acid excretion was significantly negatively correlated with the serum TC and non-HDL-C, as well as with the hepatic TC and EC. High-dose FM significantly enhanced daily faecal total bile acid excretion, which attributed to the hydrolysis of conjugated bile acids and the binding of free bile acids by the cells of strain F0822. These data suggest that the FM may serve as a functional food and has the potential to regulate cholesterol metabolism in humans.
研究领域:
营养学
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微生物学
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代谢组学
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DOI
高影响因子
Nutrients
·
2023
·Vol. 15
·期 4
·973
·
IF 5.9
Haiyan Zhou,Wenjing Liu,Yiqian Lv,Ke Liu,Yin Wang,Shuangli Meng,Tong Kang,Yuechao Bao,Huicui Meng
We aimed to examine the effect of natto and red yeast rice (NR) supplementation on lipid and lipoprotein profiles, gene expressions of cholesterol metabolism, and the composition of gut microbiota in ApoE-/-mice. Forty-one male ApoE-/-mice aged 7–8 wks old were randomly fed a control diet (CD), CD + NR (oral gavage at 0.3 g/kg BW/day), high-fat and high-cholesterol diet (HFD), or HFD + NR for 12 wks. Fasting blood samples, liver and intestine tissues and fecal samples were collected at week 12. Biochemical parameters, gene expressions in cholesterol metabolism and gut microbiota composition and diversity were measured using standard methods. NR supplementation had no significant effect on lipid and lipoprotein profiles. Compared with the HFD group, HFD + NR resulted in higher mRNA expressions of HMGCR and CYP7A1 (bothP-NR< 0.05) and ABCA1 (P-diet*NR= 0.0134,P-NR= 0.0407), lower mRNA expression of PCSK9 (P-diet*NR= 0.0002), lower fasting glucose concentrations (P-diet*NR= 0.0011), and lower relative abundance of generaBacteroidesandLactococcus(bothP-NR< 0.01) andCoriobacteriaceae_UCG-002(P-diet*NR= 0.0007). The relative abundance ofLactococcuswas inversely correlated with HMGCR and CYP7A1, and the relative abundance ofCoriobacteriaceae_UCG-002was positively correlated with PCSK9 and inversely correlated with ABCA1 (allP< 0.05). These findings suggest that NR supplementation may regulate gene expressions in cholesterol metabolism via changes in the gut microbiota in HFD-fed ApoE-/-mice.Keywords:natto;red yeast rice;gene expression;cholesterol metabolism;gut microbiota
研究领域:
营养学
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分子生物学
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胃肠病学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Anhui Wang,Xue Yang,Jiachun Lin,Yali Wang,Jinni Yang,Yuting Zhang,Yuan Tian,Haijuan Dong,Zunjian Zhang,Rui Song
Ethnopharmacological relevance Si-Ni-San (SNS), a traditional Chinese medicinal formula derived from Treatise on Febrile Diseases , is considered effective in the treatment of inflammatory bowel diseases based upon thousands of years of clinical practice. However, the bioactive ingredients and underlying mechanisms are still unclear and need further investigation. Aim of the study This study aimed to evaluate the effect, explore the bioactive ingredients and the underlying mechanisms of SNS in ameliorating ulcerative colitis (UC) and associated liver injury in dextran sodium sulphate (DSS)-induced mouse colitis models. Materials and methods The effect of SNS (1.5, 3, 6 g/kg) on 3% DSS-induced acute murine colitis was evaluated by disease activity index (DAI), colon length, inflammatory cytokines, hematoxylin-eosin (H&E) staining, tight junction proteins expression, ALT, AST, and oxidative stress indicators. HPLC-ESI-IT/TOF MS was used to analyze the chemical components of SNS and the main xenobiotics in the colon of UC mice after oral administration of SNS. Network pharmacological study was then conducted based on the main xenobiotics. Flow cytometry and immunohistochemistry techniques were used to demonstrate the inhibitory effect of SNS on Th17 cells differentiation and the amelioration of Th17/Treg cell imbalance. LC-MS/MS, Real-time quantitative polymerase chain reaction (RT-qPCR), and western blotting techniques were performed to investigate the oxysterol-Liver X receptor (LXRs) signaling activity in colon. Targeted bile acids metabolomics was conducted to reveal the change of the two major pathways of bile acid synthesis in the liver, and the expression of key metabolic enzymes of bile acids synthesis was characterized by RT-qPCR and western blotting techniques. Results SNS (1.5, 3, 6 g/kg) decreased the DAI scores, protected intestinal mucosa barrier, suppressed the production of pro-inflammatory cytokines, improved hepatic and splenic enlargement and alleviated liver injury in a dose-dependent manner. A total of 22 components were identified in the colon of SNS (6 g/kg) treated colitis mice, and the top 10 components ranked by relative content were regarded as the potential effective chemical components of SNS, and used to conduct network pharmacology research. The efficacy of SNS was mediated by a reduction of Th17 cell differentiation, restoration of Th17/Treg cell homeostasis in the colon and spleen, and the experimental results were consistent with our hypothesis and the biological mechanism predicted by network pharmacology. Mechanistically, SNS regulated the concentration of 25-OHC and 27-OHC by up-regulated CH25H, CYP27A1 protein expression in colon, thus affected the expression and activity of LXR, ultimately impacted Th17 differentiation and Th17/Treg balance. It was also found that SNS repressed the increase of hepatic cholesterol and reversed the shift of BA synthesis to the acidic pathway in UC mice, which decreased the proportion of non-12-OH BAs in total bile acids (TBAs) and further ameliorated colitis and concomitant liver injury. Conclusions This study set the stage for considering SNS as a multi-organ benefited anti-colitis prescription based on the significant effect of ameliorating intestinal and liver damage, and revealed that derivatives of cholesterol, namely oxysterols and bile acids, were closely involved in the mechanism of SNS anti-colitis effect.
研究领域:
中药学
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药理学
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免疫学
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DOI
PubMed
高影响因子
Marine Drugs
·
2021
·Vol. 19
·期 9
·485
·
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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PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
·
IF 2.5
Qihan Wang,Weiyi Shen,Wentao Shao,Hai Hu
Berberine (BBR) is a traditional Chinese herb with broad antimicrobial activity . Gut microbiota plays an important role in the metabolism of bile acids and cholesterol. Our study investigated the effects of BBR on alleviating cholesterol and bile acid metabolism disorders induced by high cholesterol diet in mice. Adult male C57BL/6J mice fed with high cholesterol diet (HC) containing 1.25 % cholesterol (HC group) or fed with chow diet containing 0.02 % cholesterol (Chow group) served as controls. BBR50 and BBR100 group mice were fed with HC, and oral BBR daily at doses of 50 or 100 mg/kg respectively for 8 weeks. The results showed that BBR could reshape the homeostasis and composition of gut microbiota. The abundance of Clostridium genera was significantly inhibited by BBR, which resulted in a significant reduction of secondary bile acids within the enterohepatic circulation and a significant lower hydrophobic index of bile acids . The absorption of cholesterol in intestine, the deposition of cholesterol in liver and the excretion of cholesterol in biliary tract were significantly inhibited by BBR, which promoted the unsaturation of cholesterol in bile. These findings suggest the potential utility of BBR as a functional food to alleviate the negative effects of high cholesterol diet.
研究领域:
营养学
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微生物学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF LIPID RESEARCH
·
2020
·Vol. 61
·期 4
·580-586
·
IF 4.483
Teng-Fei Yuan (袁;腾;飞,Juan Le (乐;娟,Shao-Ting Wang (王;少;亭,Yan Li (李;艳
Analyzing global steroid metabolism in humans can shed light on the etiologies of steroid-related diseases. However, existing methods require large amounts of serum and lack the evaluation of accuracy. Here, we developed an LC/MS/MS method for the simultaneous quantification of 12 steroid hormones: testosterone, pregnenolone, progesterone, androstenedione, corticosterone, 11-deoxycortisol, cortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, estriol, and estradiol. Steroids and spiked internal standards in 100 μl serum were extracted by protein precipitation and liquid-liquid extraction. The organic phase was dried by evaporation, and isonicotinoyl chloride was added for steroid derivatization, followed by evaporation under nitrogen and redissolution in 50% methanol. Chromatographic separation was performed on a reverse-phase PFP column, and analytes were detected on a triple quadrupole mass spectrometer with ESI. The lower limits of quantification ranged from 0.005 ng/ml for estradiol to 1 ng/ml for cortisol. Apparent recoveries of steroids at high, medium, and low concentrations in quality control samples were between 86.4% and 115.0%. There were limited biases (−10.7% to 10.5%) between the measured values and the authentic values, indicating that the method has excellent reliability. An analysis of the steroid metabolome in pregnant women highlighted the applicability of the method in clinical serum samples. We conclude that the LC/MS/MS method reported here enables steroid metabolome analysis with high accuracy and reduced serum consumption, indicating that it may be a useful tool in both clinical and scientific laboratory research.
研究领域:
临床医学
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分析化学
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PubMed
高影响因子
Nutrients
·
2024
·Vol. 16
·期 13
·2002
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IF 4.8
Haijuan Hu,Peipei Zhang,Fengxia Liu,Siyi Pan
(1) Background: Recently, academic studies are demonstrating that the cholesterol-lowering effects of pectin oligosaccharides (POSs) are correlated to intestinal flora. However, the mechanisms of POS on cholesterol metabolisms are limited, and the observations of intestinal flora are lacking integrative analyses. (2) Aim and methods: To reveal the regulatory mechanisms of POS on cholesterol metabolism via an integrative analysis of the gut microbiota, the changes in gut microbiota structure and metabolite composition after POS addition were investigated using Illumina MiSeq sequencing and non-targeted metabolomics through in vitro gut microbiota fermentation. (3) Results: The composition of fecal gut flora was adjusted positively by POS. POS increased the abundances of the cholesterol-related bacterial groupsBacteroidetes,BifidobacteriumandLactobacillus, while it decreased conditional pathogenicEscherichia coliandEnterococcus, showing good prebiotic activities. POS changed the composition of gut microbiota fermentation metabolites (P24), causing significant changes in 221 species of fermentation metabolites in a non-targeted metabolomics analysis and promoting the production of short-chain fatty acids. The abundances of four types of cholesterol metabolism-related metabolites (adenosine monophosphate, cyclic adenosine monophosphate, guanosine and butyrate) were significantly higher in the P24 group than those in the control group without POS addition. (4) Conclusion: The abovementioned results may explain the hypocholesterolemic effects of POS and promotion effects on cholesterol efflux of P24. These findings indicated that the potential regulatory mechanisms of citrus POS on cholesterol metabolism are modulated by cholesterol-related gut microbiota and specific metabolites.
研究领域:
微生物学
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营养学
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代谢组学
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胃肠病学
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DOI
PubMed
高影响因子
NEURON
·
2025
·
IF 15
Tao Qin,Tao Jiang,Zihan Zhou,Mengyuan Wu,Yuanzhen Zhang,Zhenqi Yang,Ziyang Zheng,Jiang Yi,Xiaowei Wang,Mingran Luo,Peng Gao,Jiayun Liu,Yifan Huang,Hao Liu,Qingqing Li,Wei Zhou,Shujun Zhang,Xiaodong Guo,Baorong He,Yongxiang Wang,Jin Fan,Shujie Zhao,Jian Chen,Guoyong Yin
The spatiotemporal dynamics and specific roles of regulatory T (Treg) cells in spinal cord injury (SCI) remain unclear. Using single-cell RNA sequencing, flow cytometry, and immunofluorescence, we found that thymus-derived Treg cells infiltrate the injured spinal cord via peripheral blood around 3 days post-SCI. Treg cell depletion worsened SCI and impaired long-term recovery. Transcriptomic profiling revealed strong anti-inflammatory functions of Treg cells and the potential to regulate cholesterol metabolism in neighboring microglia. Further single-cell RNA sequencing uncovered the clonality of SCI-associated Treg cells. Major histocompatibility complex class II (MHC II) expression on microglia, not macrophages, was crucial for sustaining Treg cell numbers and neuroprotective function, with myelin-phagocytosing microglia-activated Treg cells showing significant neuroprotective effects. Treg cells mitigated microglial inflammation via CTLA-4 and upregulated the ATP-binding cassette transporter G1 (Abcg1) receptor in microglia, helping to manage myelin load and reduce lipid droplet formation. Our findings offer mechanistic insights into SCI-associated Treg cells and lay the groundwork for future Treg-based therapies in SCI treatment.
研究领域:
免疫学
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神经科学
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分子生物学
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转化医学
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炎症与修复
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神经免疫学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 26
·期 1
·77
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IF 4.9
Zhiting Guo,Huiyan Yu,Kexin Yang,Wenjing Feng,Miao Liu,Tao Wang,Rong Xiao
Oxysterols, as metabolites of cholesterol, play a key role in cholesterol homeostasis, autophagosome formation, and regulation of immune responses. Disorders in oxysterol metabolism are closely related to the pathogenesis of neurodegenerative diseases. To systematically investigate the profound molecular regulatory mechanisms of neurodegenerative diseases, it is necessary to quantify oxysterols and their metabolites in central and peripheral biospecimens simultaneously and accurately. However, there are a lot of unsolved problems with the existing methods, such as the hindrance of applying a single method to different biological specimens or the challenge of simultaneous quantification due to differential groups on the ends of the oxysterol side chains. Herein, according to the physicochemical properties and structure of oxysterols, an optimized liquid chromatography-tandem mass spectrometry method for the quantification of oxysterols was established by optimizing the sample preparation process, chromatographic conditions, mobile phase pH, and solvent selection. Seven oxysterols were detected by this method, including 27-hydroxycholesterol, 7α-hydroxycholesterol, 7α,27-dihydroxycholesterol, 7-dehydrocholesterol, 7α-hydroxy-3-oxo-4-cholestenoic acid, 3-hydroxy-5-cholestenoic acid, and 24(S)-hydroxycholesterol. Non-derivatization extraction with methyl tert-butyl ether was used for different biospecimens, followed by simultaneous chromatographic separation of oxysterols on a phenyl hexyl column. By repeated validation, this method exhibited satisfactory linearity, precision, recovery, sensitivity, repeatability, and stability, and it was successfully applied to the detection of oxysterols in the plasma, cerebral cortex, and liver of mouse. In summary, our optimized method enables concurrent analysis and quantification of oxysterols and their metabolites in various biospecimens, presenting a broad range of applicability.
研究领域:
生物化学
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医学分析
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神经科学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）