JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS
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2020
·Vol. 108
·期 8
·3331-3344
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IF 2.831
Jiaojun Wei,Dongmei Lei,Maohua Chen,Pan Ran,Xiaohong Li
In vitro cell and tissue models are playing essential roles in the identification of active pharmaceutical ingredients. Though HepG2 cells have attractive profiles over primary hepatocytes in the availability and viability retention, the expression of metabolizing enzymes is quite low. In the current study, three-dimensional (3D) HepG2 spheroids with smaller sizes of 150 μm (3Ds) and bigger sizes of 300 μm (3Db) are engineered using injectable fiber fragments as the substrate. In contrast to two-dimensional (2D) culture, the enzyme activities for drug metabolisms are restored in 3Ds and the pathophysiological profiles of tumor tissues are rebuilt in 3Db spheroids. Compared with spheroid culture without fiber fragments, 3Ds spheroids show higher activities of metabolizing enzymes (CYP3A4, CYP2A9, and phase II) and higher sensitivities to enzyme inducers (rifampicin and glutathione) and inhibitors (ketoconazole and probenecid). The drug clearance and toxicity to 3Ds spheroids predict better the clinical observations and drug–drug interactions. In addition, compared to scaffold-free spheroid culture, stronger expressions of E-cadherin and hypoxia-inducible factor-1α (HIF-1α) and higher fibronectin secretions are determined in 3Db spheroids, displaying apparent hypoxic and apoptotic regions similar to those found in solid tumors. In contrast to the overestimated drug toxicity in other systems, the infiltrations of free drug and drug-loaded micelles are apparently restricted in 3Db spheroids, exhibiting drug resistance just like in tumor tissues. Thus, this study demonstrates HepG2 spheroids with different sizes as predictable and physiologically relevant models for high-throughput screening of drug metabolism and tumor infiltration.
研究领域:
药学
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生物医学工程
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细胞生物学
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组织工程
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产品关联
DOI
PubMed
高影响因子
CURRENT DRUG METABOLISM
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2024
·Vol. 25
·期 10
·754-768
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IF 2.1
Xiaoyun Liu,Dafang Zhong,Chongzhuang Tang,Xiaofeng Xu,Hong Lan,Xingxing Diao
Background BPI-460372 is an orally available, covalent, irreversible small molecule inhibitor of the transcriptional enhanced associate domain (TEAD) 1/3/4, which is currently in clinical development for the treatment of cancers with Hippo pathway alterations. Objectives This study aimed to determine the cytochrome P450 (CYP) phenotyping, metabolic stability, and in vitro and in vivo metabolic profile of BPI-460372. Methods The CYP phenotyping and metabolic stability were assessed by measuring the depletion of substrate. The metabolic profile in hepatocytes and rat and dog plasma was analyzed using ultra-high-performance liquid chromatography combined with Orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS). Results BPI-460372 was mainly metabolized by CYP2D6, CYP3A4, and CYP1A2. BPI-460372 exhibited low clearance in human, monkey, and rat hepatocytes, while moderate clearance in dog and mouse hepatocytes. A total of 10 metabolites were identified in five species of hepatocytes, and no human-unique metabolite was detected. In rat plasma and dog plasma, the primary metabolites were M407 (BPI-460430) and M423 (BPI-460456), respectively. The two metabolites were quantitatively determined in rat and dog plasma in pharmacokinetic and toxicological studies. The major metabolic site was 2-fluoro-acrylamide, and major metabolic pathways in hepatocytes, and rat and dog plasma involved oxidative defluorination, hydration, glutathione (GSH) conjugation, hydrolysis, cysteine conjugation, and N-acetyl cysteine conjugation. β-lyase pathway contributed to the metabolism of BPI-460372 in rats to a certain degree. Conclusion This study elucidated the metabolism of BPI-460372 and provided a basis for pharmacokinetic and toxicological species selection, human pharmacokinetics prediction, and assessment of clinical co-administration limitations and possible metabolic pathways in humans.
研究领域:
药理学
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药物代谢
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肿瘤学
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生物化学
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临床药理学
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分析化学
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毒理学
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分子生物学
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DOI
高影响因子
Expert Opinion on Drug Delivery
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2020
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IF 4.838
Yidi Ma,Rou Guan,Shuying Gao,Wei Song,Yubo Liu,Yang Yang,Hongzhuo Liu
Introduction Everolimus (EVR) has been approved for the treatment of various advanced cancers and its indications are increasingly expanding. Therefore, it is crucial for patients who have difficulty in swallowing, such as pediatric and elderly patients, to obtain a convenient formulation. The oral absorption of EVR is limited due to its low solubility in water, intestinal metabolism by CYP3A4 enzyme, P-gp-mediated efflux, and metabolism in the liver. The aim of this study was to develop a novel sublingual orodispersible film loading everolimus for improving patient compliance and enhancing oral bioavailability of EVR.Research design and methods Sublingual orodispersible films loading EVR were prepared by the solvent casting method and evaluated by in vitro and in vivo studies.Results The properties of films were determined by scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectrometry. The addition of acacia gum appeared to be crucial for protecting the drug from oxidation. Pharmacokinetic studies showed that loading into the sublingual orodispersible films significantly increased the oral bioavailability of EVR.Conclusion The EVR-loaded sublingual orodispersible films are a promising, economical, and convenient approach for delivering EVR efficiently in a solid dosage form.
研究领域:
药学
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药物递送系统
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药理学
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产品关联
DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
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2019
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IF 4.959
Wei Liu,Mi Zhang,Miaomiao Zhou,Ce Gu,Zhaoyang Ye,Yan Xiao,Yan Zhou,Meidong Lang,Wen-Song Tan
For hepatocyte culture in vitro , the surface feature of utilized scaffolds exerts a direct impact on cell adhesion, growth and differentiated functionality. Herein, to regulate hepatocyte growth and differentiated functionality, modified microfibrous scaffolds were fabricated by surface grafting monoamine terminated lactobionic lactone ( L -NH 2 ) and gelatin onto non-woven poly(ethylene terephthalate) (PET) fibrous substrate (PET-Gal and PET-Gel), respectively. The physicochemical properties of PET scaffolds before and after modification were characterized. Upon 15-day culture, the effects of modified PET scaffolds on growth and differentiated functionality of human induced hepatocytes (hiHeps) were evaluated, compared with that of control without modification. Results demonstrated that both L -NH 2 and gelatin modifications improved scaffold properties including hydrophilicity, water uptake ratio, stiffness and roughness, resulting in efficient cell adhesion, ~20-fold cell expansion and enhanced differentiated functionality. After culture for 15 days, PET-Gal cultured cells formed aggregates, displaying better cell viability and significantly higher differentiated functionality regarding albumin secretion, urea synthesis, phases I (cytochrome P450, CYP1A1/2 and CYP3A4) and II (uridine 5′-diphosphate glucuronosyltransferases, UGT) enzyme activity, biliary excretion and detoxification ability (ammonia elimination and bilirubin conjugation), compared with PET and PET-Gel cultured ones. Hence, as a three-dimensional (3D) microfibrous scaffold, PET-Gal promotes hiHeps growth and differentiated functionality maintenance, which is promisingly utilized in bioartificial liver (BAL) bioreactors.
研究领域:
生物医学工程
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细胞生物学
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组织工程
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再生医学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
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IF 6.7
Shanyi Yang,Zhijuan Wei,Jichu Luo,Xuancheng Wang,Guanghui Chen,Xuan Guan,Zhiyong She,Wenhui Liu,Ying Tong,Huan Liu,Mingsen Wen,Hongwei Chen,Pingchuan Zhu,Gui Li,Dongling Wang,Lin Huang,Siyi Xu,Danying Chen,Qisong Zhang,Ye Wei
Background Non-alcoholic fatty liver disease (NAFLD) poses a significant global public health concern. Liupao tea (LPT) is a Chinese national geographical indication product renowned for its lipid-lowering properties. However, the precise mechanisms and active constituents contributing to the efficacy of LPT against NAFLD remain unclear. Purpose This study aims to comprehensively explore the therapeutic potential of Liupao tea extract (LPTE) in alleviating NAFLD through an integrated strategy. Methods Initially, network pharmacology analysis was conducted based on LPTE chemical ingredient analysis, identifying core targets and key components. Potential active ingredients were validated through chemical standards based on LC-MS/MS. To confirm the pharmacological efficacy of LPTE in NAFLD, NAFLD mice models were employed. Alterations in hepatic lipid metabolism were comprehensively elucidated through integration of metabolomics, lipidomics, network pharmacology analysis, and real-time PCR analysis. To further explore the binding interactions between key components and core targets, molecular docking and microscale thermophoresis (MST) analysis were employed. Furthermore, to investigate LPTE administration effectiveness on gut microbiota in NAFLD mice, a comprehensive approach was employed. This included Metorigin analysis, 16S rRNA sequencing, molecular docking, and fecal microbiome transplantation (FMT). Results Study identified naringenin, quercetin, luteolin, and kaempferol as the potential active ingredients of LPTE. These compounds exhibited therapeutic potential for NAFLD by targeting key proteins such as PTGS2, CYP3A4, and ACHE, which are involved in the metabolic pathways of hepatic linoleic acid (LA) and glycerophospholipid (GP) metabolism. The therapeutic effectiveness of LPTE was observed to be comparable to that of simvastatin. Furthermore, LPTE exhibited notable efficacy in alleviating NAFLD by influencing alterations in gut microbiota composition ( Proteobacteria phylum, Lactobacillus and Dubosiella genus) that perhaps impact LA and GP metabolic pathways. Conclusion LPTE could be effective in preventing high-fat diet (HFD)-induced NAFLD by modulating hepatic lipid metabolism and gut microbiota. This study firstly integrated bioinformatics and multi-omics technologies to identify the potential active components and key microbiota associated with LPTE's effects, while also primally elucidating the action mechanisms of LPTE in alleviating NAFLD. The findings offer a conceptual basis for LPTE's potential transformation into an innovative pharmaceutical agent for NAFLD prevention.
研究领域:
药理学
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生物信息学
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代谢组学
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脂质组学
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胃肠病学
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微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）