Foods
·
2024
·Vol. 13
·期 8
·1194
·
IF 4.7
Yulong Wu,Jin Zhang,Ruikai Zhu,Hong Zhang,Dapeng Li,Huanhuan Li,Honggang Tang,Lihong Chen,Xinyan Peng,Xianrong Xu,Ke Zhao
Two novel dipeptidyl peptidase IV (DPP-IV) inhibitory peptides (YPF and LLLP) were discovered from goat milk protein by peptidomics, in silico analysis, and in vitro assessment. A total of 698 peptides (<23 AA) were successfully identified by LC-MS/MS from goat milk hydrolysates (hydrolyzed by papaian plus proteinase K). Then, 105 potential DPP-IV inhibitory peptides were screened using PeptideRanker, the ToxinPred tool, Libdock, iDPPIV-SCM, and sequence characteristics. After ADME, physicochemical property evaluation, and a literature search, 12 candidates were efficiently selected and synthesized in vitro for functional validation. Two peptides (YPF and LLLP) were found to exert relatively high in vitro chemical system (IC50= 368.54 ± 12.97 μM and 213.99 ± 0.64 μM) and in situ (IC50= 159.46 ± 17.40 μM and 154.96 ± 8.41 μM) DPP-IV inhibitory capacities, and their inhibitory mechanisms were further explored by molecular docking. Our study showed that the formation of strong non-bonding interactions with the core residues from the pocket of DPP-IV (such as ARG358, PHE357, GLU205, TYR662, TYR547, and TYR666) might primarily account for the DPP-IV inhibitory activity of two identified peptides. Overall, the two novel DPP-IV inhibitory peptides rapidly identified in this study can be used as functional food ingredients for the control of diabetes.
研究领域:
生物化学
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药理学
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食品科学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2020
·
IF 4.845
Tian'e Chen,Liangxing Tu,Ge Wang,Na Qi,Wei Wu,Wei Zhang,Jianfang Feng
Chitosan is widely used as a permeation enhancer for oral drug delivery, although its drawbacks include a limited enhancement of drug bioavailability and an inability to form micelles. In this study, we designed a novel chitosan derivative (GA-CS-TPGS copolymer) and constructed paclitaxel micelles (PTX-Micelles) designed to have multiple functions associated with the GA-CS-TPGS copolymer (enhanced bioadhesion, inhibited P-gp efflux and drug metabolism in liver) and the micelles (enhanced solubility and permeability) to enhance the bioavailability and anti-tumor efficacy of PTX. The results showed that the PTX-Micelles system could alter the in vivo pharmacokinetic performance and therapeutic effect of PTX via its predesigned functions. The bioavailability of PTX was enhanced approximately 3.80-fold by the PTX-Micelles, and an enhanced anti-lung tumor efficacy of PTX-Micelles was observed when compared to Taxol®. The results of this study indicate that constructing micelles with a multifunctional chitosan derivative may be a promising approach to enhance the oral bioavailability and anti-tumor efficacy of poorly soluble drugs.
研究领域:
药剂学
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药物递送系统
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药理学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS
·
2020
·Vol. 108
·期 8
·3331-3344
·
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
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
·
2019
·Vol. 411
·期 18
·4025-4030
·
IF 3.286
Li Hao-Wen,Hua Xin,Long Yi-Tao
Time-of-flight secondary ion mass spectrometry (ToF-SIMS) has shown promising applications in single-cell analysis owing to its high spatial resolution molecular imaging capability. One of the main drawbacks hindering progress in this field is the relatively low ionization efficiency for biological systems. The complex chemical micro-environment in single cells typically causes severe matrix effects, leading to significant signal suppression of biomolecules. In this work, we investigated the signal enhancement effect of graphene quantum dots (GE QDs) in ToF-SIMS analysis. A × 160 magnification of ToF-SIMS signal for amiodarone casted on glass slide was observed by adding amino-functionalized GE QDs (amino-GE QDs), which was significantly higher than adding previously reported signal enhancement materials and hydroxyl group-functionalized GE QDs (hydroxyl-GE QDs). A possible mechanism for GE QD-induced signal enhancement was proposed. Further, effects of amino-GE QDs and hydroxyl-GE QDs on amiodarone-treated breast cancer cells were compared. A significant signal improvement for lipids and amiodarone was achieved using both types of GE QDs, especially for amino-GE QDs. In addition, ToF-SIMS chemical mapping of single cells with better quality was obtained after signal enhancement. Our strategy for effective ToF-SIMS signal enhancement holds great potential for further investigation of drug metabolism pathways and the interactions between the cell and micro-environment.
研究领域:
分析化学
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生物医学工程
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材料科学
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细胞生物学
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药学
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产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2022
·Vol. 14
·期 11
·2307
·
IF 6.525
Xueyan Gou,Fenglin Ran,Jinru Yang,Yanrong Ma,Xin’an Wu
Background: Organic anion transporter 1 (OAT1) and OAT3 have an overlapping spectrum of substrates such that one can exert a compensatory effect when the other is dysfunctional. As a result, the knockout of either OAT1 or OAT3 is not reflected in a change in the excretion of organic anionic substrates. To date, only the mOAT1 and mOAT3 individual knockout mouse models have been available. Methods: In this study, we successfully generated aSlc22a6/Slc22a8double-knockout (KO) rat model using CRISPR/Cas9 technology and evaluated its biological properties. Results: The double-knockout rat model did not expressionmRNAfor rOAT1 or rOAT3 in the kidneys. Consistently, the renal excretion ofp-aminohippuric acid (PAH), the classical substrate of OAT1/OAT3, was substantially decreased in theSlc22a6/Slc22a8double-knockout rats. The relativemRNAlevel ofSlco4c1was up-regulated in KO rats. No renal pathological phenotype was evident. The renal elimination of the organic anionic drug furosemide was nearly abolished in theSlc22a6/Slc22a8knockout rats, but elimination of the organic cationic drug metformin was hardly affected. Conclusions: These results demonstrate that this rat model is a useful tool for investigating the functions of OAT1/OAT3 in metabolic diseases, drug metabolism and pharmacokinetics, and OATs-mediated drug interactions.Keywords:OAT1/OAT3;CRISPR/Cas9;gene knockout;pharmacokinetic
研究领域:
药理学
·
分子生物学
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遗传学
·
药物发现
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL ENGINEERING JOURNAL
·
2020
·
IF 3.475
Wei Liu,Mi Zhang,Yan Xiao,Zhaoyang Ye,Yan Zhou,Meidong Lang,Wen-Song Tan
Bioartificial liver (BAL) comprising a functional bioreactor represents a promising treatment, bridging patients with acute liver failure (ALF) to liver transplantation. In this research, a packed-bed (PB) bioreactor by utilizing galactosylated poly(ethylene terephthalate) microfibrous carrier (PET-Gal) was fabricated and evaluated in vitro . Human induced hepatocytes (hiHeps) were dynamically seeded into a PET-Gal loaded bioreactor and cultured for 10 days. During perfusion culture, the effects of bioreactor scaffold on hepatocyte seeding, growth and functionality (albumin secretion and urea production) were determined, compared with that of control with non-modified PET carrier. Afterwards, drug metabolism and detoxification ability of hiHeps were measured. Results demonstrated that the seeding rate and proliferation fold within PET-Gal loaded bioreactor were significantly higher than that of control, resulting in a cell density of (8.17 ± 0.52)×10 7 cells/cm 3 . In contrast to flattened morphology observed in the control, hiHeps cultured in PET-Gal based bioreactor displayed as three-dimensional (3D) cell aggregates with close cell-matrix and cell-cell interactions and high cell viability, leading to higher albumin secretion and urea production. Besides, there were high levels of phase I drug metabolism and ammonia elimination for PET-Gal cultured cells. Therefore, the PET-Gal based PB bioreactor fabricated herein supports high-density hepatocyte growth and meanwhile preserves hepatic functionality, showing great potential in BAL systems application.
研究领域:
生物医学工程
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组织工程
·
肝病学
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产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Xinxu Yan,Baolong Feng,Hongjie Song,Lili Wang,Yehui Wang,Yulin Sun,Xiaoshuang Cai,Yating Rong,Xibo Wang,Yutang Wang
Natural Xanthine oxidase (XOD) inhibitors represent promising therapeutic agents for hyperuricemia (HUA) treatment due to their potent efficacy and favorable safety profiles. This study involved the construction of a comprehensive database of 315 XOD inhibitors and development of 28 machine learning-based QSAR models. The ChemoPy light gradient boosting machine model exhibited the best performance (AUC = 0.9371 and MCC = 0.7423). This model identified three potential XOD inhibitors from the FooDB database: daphnetin, 7-hydroxycoumarin, and piceatannol. Molecular docking and dynamics simulations revealed favorable interactions, with piceatannol showing a remarkable stability through hydrogen bonding and hydrophobic interactions. ADME predictions suggested that all three compounds possess desirable drug-like properties and safety characteristics. Subsequent in vitro enzyme inhibition assays validated computational predictions, with piceatannol exhibiting the strongest inhibitory activity (IC 50 = 8.80 ± 0.05 μM). Multispectroscopic analyses revealed that piceatannol–XOD binding was predominantly mediated by hydrogen bonding and van der Waals forces, which induced conformational changes characterized by decreased α-helical content and increased proportions of β-sheets, β-turns, and random coils. This study presents an efficient strategy for the identification of natural XOD inhibitors, elucidates the molecular mechanism of piceatannol-mediated XOD inhibition, and establishes a foundation for its therapeutic application in HUA treatment.
研究领域:
药理学
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药物化学
·
生物信息学
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分子生物学
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药物发现
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Yao Yao,Yue Zhao,Huijuan Zhang,Wenting Pan,Wei Liang,Yijian Jiang,Xinlong Yan,Yinzhou Yan
The development of surface-enhanced Raman spectroscopy (SERS) as an ultrasensitive fingerprint analysis technique in precision medicine requires high-performance SERS substrates with controllable nanostructure (hot-spot) distribution, simple fabrication, superior stability, biocompatibility, and extraordinary optical responses. Unfortunately, fabrication of arbitrary nanostructures with high homogeneity on a large scale for SERS is still challenging. Herein, we report an ultrafast laser parallel fabrication protocol for Au/2D-transition-metal dichalcogenide hybrid SERS biosensors. The leveraged photonic nanojets (PNJs) are generated by a micron-sized microsphere monolayer to simultaneously trigger localized phase transition in 2H-MoTe2, achieving a 1T′-MoTe2 nanopattern array with a density of 1 million per mm2 by a single laser shot. The Au nanoparticle clusters (AuNCs) are subsequently grown in situ from the 1T′ regions, creating a AuNCs on 1T′/2H-MoTe2 (AuNCs@1T’/2H-MoTe2) hybrid SERS substrate. The fabricated feature diameter and overlay accuracy of the patterned AuNCs are 210.1 ± 3.4 and 9.2 ± 1.7 nm, respectively. To eliminate background noise, we designed dimer-AuNCs@1T′/2H-MoTe2 (dAuNCs@1T′/2H-MoTe2), achieving a detection limit of 10–13 M with an enhancement factor of 4.9 × 108 for the methylene blue (MB) analyte. The strong localized surface plasmon resonances in the dAuNCs as well as efficient charge transfers between Au, 2H-MoTe2, and MB contribute to the majority of Raman enhancement. The multiscale dAuNCs@1T′/2H-MoTe2 array provides a powerful SERSome (comprising multiple SERS spectra) platform for therapeutic drug monitoring, by which we successfully identified the metabolic behaviors of living gastric adenocarcinoma cells administered with two drugs, i.e., capecitabine, oxaliplatin, and their combination. The present work establishes opportunities for creating a highly ordered nanopattern array for ultrasensitive SERSome analysis of cell metabolism in cancer therapy.
研究领域:
纳米技术
·
生物医学工程
·
分析化学
·
癌症研究
·
材料科学
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光学与光子学
·
精准医学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2019
·
IF 4.527
Shengxian Liang,Shaojun Liang,Nuoya Yin,Francesco Faiola
The liver is one of the major targets of hormones, including thyroid hormones (THs), and many industrial chemicals, such as endocrine-disrupting chemicals. Those compounds may permeate the placenta barrier and pose a risk for embryonic development . Therefore, it is necessary to assess the toxic effects of those kind of industrial chemicals during liver development. In this study, to mimic liver specification in vitro, we differentiated human embryonic stem cells (ESCs) into functional hepatocyte-like cells. We performed this differentiation process in presence of two THs, triiodothyronine (T3) and thyroxine (T4), with the purpose of identifying biomarkers for toxicity screening. TH exposure (3, 30 and 300 nM) yielded to hepatocytes with impaired glycogen storage ability and abnormal lipid droplets’ accumulation. Global gene expression analysis by RNA-seq identified a number of genes responsible for hepatic differentiation and function which were affected by 30 nM T3 and T4. Those differentially expressed genes were used to assess the potential developmental liver toxicity of two famous environmental pollutants, 2, 2, 4, 4-tetrabromodiphenyl ether (BDE-47) and decabromodiphenyl ether (BDE-209), at 10 nM to 1 μM treatments. Our findings demonstrate that BDE-47 and BDE-209, dysregulated pathways such as “chemical carcinogenesis”, “steroid hormone biosynthesis” and “drug metabolism-cytochrome P450”. Moreover, we were able to identify a set of 17 biomarkers, very useful to predict the potential developmental hepatotoxicity of industrial chemicals.
研究领域:
毒理学
·
干细胞生物学
·
发育生物学
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环境科学
·
药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Zhijian Lu,Junqing Zhao,Wei Xiao,Zhujun Wang,Qi Ren,Xiaofang Huang,Hui Ouyang,Yulin Feng
Ethnopharmacological relevance N-[2-(1-β-D-Glucopyranosyl-1H-indol-3-yl)acetyl]-L-aspartic acid (GK-A), N-[2-(1-β-D-Glucopyranosyl-1H-indol-3-yl)acetyl]-L-glutamic acid (GK-2) and Eucomic acid are the main active components of Ginkgo Semen , which have strong antitussive effects. However, the pharmacokinetics, tissue distribution, metabolism, and in vitro liver microsome stability of these components in rats remain unstudied. Aim of the study Comprehensive evaluation of the pharmacokinetics, tissue distribution, in vitro liver microsomal stability, and in vivo metabolic behavior of GK-A, GK-2, and Eucomic acid in Ginkgo Semen extract (GSE). Materials and methods A very rapid and highly sensitive LC-MS/MS approach was established to study the pharmacokinetics of orally administered GSE (80 mg/kg) and quantify GK-A, GK-2, and Eucomic acid in various tissues. DESI-MSI was utilized to clearly visualize the spatial distribution of GK-A, GK-2, and Eucomic acid in lung tissue, while UPLC-Q-TOF-MS analyzed the metabolic profiles of GK-A, GK-2, and Eucomic acid in rat plasma and excreta. Results GK-A, GK-2, and Eucomic acid reached T max within 2 h, with MRT 0-t under 4 h following oral GSE administration. GK-A and GK-2 were present in all tissues except the brain, while Eucomic acid was also detected in brain tissue. All three compounds showed high concentrations in the small intestine, kidneys, stomach, and liver. They were metabolized slowly and poorly in liver microsomes from cynomolgus monkeys, rats, dogs, and humans. In total, 14 GK-A metabolites, 8 GK-2 metabolites, and 8 Eucomic acid metabolites were identified in plasma, urine, and feces. Conclusions GK-A, GK-2 and Eucomic acid were all rapidly absorbed by plasma and widely distributed in tissues after oral administration of GSE. There was no accumulation of GK-A, GK-2 and Eucomic acid in the tissues, and the content in the small intestine, kidney, stomach and liver was higher. And Eucomic acid was able to cross the blood-brain barrier, and CYP450 enzyme in the liver was not the main metabolizing enzyme of the extract. GK-A, GK-2 and Eucomic acid were excreted in the feces and urine of the rats, and at the same time, were converted into other metabolites by the rats to be eliminated from the body. The results of this study lay a foundation for the further development and application of GSE.
研究领域:
药理学
·
分析化学
·
天然产物研究
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民族药理学
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药物代谢
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生物分析化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2025
·
IF 3.1
Yuqing Zhao,Yue Yang,Mingshe Zhu,Chongzhuang Tang
Metabolite profiling and identification of oligonucleotide-based therapeutics (OBTs) is important in drug discovery and development. Conventional liquid chromatography-high resolution mass spectrometry (LC-HRMS) methods (using ProMass, BioPharma Finder) are effective for targeted analysis of predictable nuclease-derived metabolites but often miss unexpected non-nuclease-mediated ones. This study aimed to develop a universal analytical workflow for comprehensive metabolite profiling of multiple classes OBTs by integrating BioPharma Finder for targeted identification with a Background Subtraction Filter (BSF) for untargeted detection of unexpected biotransformation products. Inclisiran, a GalNAc-conjugated siRNA, was used as a model compound. Samples incubated with rat, monkey, and human liver S9 fractions were analyzed by the LC-HRMS workflow. As a result, a total of 25 (22 predicted +3 unpredicted) inclisiran metabolites were identified across the three species. BioPharma Finder enabled rapid and sensitive identification of 22 predicted metabolites, supported by automated fragment ion assignment. The BSF data processing revealed 22 metabolites not present in control samples, including SS-1GalNAc, SS-2GalNAc, and SS-3GalNAc, which were missed by BioPharma Finder and likely formed via β- N -acetylglucosaminidase-mediated biotransformation. The structures of BSF-detected metabolites were confirmed by comparison with BioPharma Finder-identified metabolites or characterized through manual MS/MS interpretation. Product ion spectra of these metabolites showed weak or absent diagnostic ion ( m / z 94.936), a characteristic fragment of phosphorothioate-containing oligonucleotides, suggesting that the product ion filtering of this ion exhibits limited utility in discovering inclisiran metabolites. Overall, the integrated LC-HRMS workflow shows strong potential as a universal platform for biotransformation studies of OBTs.
研究领域:
药物分析
·
代谢组学
·
药物代谢
·
生物治疗
·
质谱分析
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寡核苷酸治疗
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产品关联
DOI
PubMed
高影响因子
Pharmacology Research & Perspectives
·
2025
·Vol. 13
·期 6
·e70189
·
IF 2.3
Bo Wang,Xu Ma,Xinggao Wang,Yuxuan Chen,Quan Zhou,Abdullah Al Mamun,Guozhen Wang,Shuanghu Wang,Xiaoxin Ma
Efavirenz (EFV) is the first-line treatment for acquired immunodeficiency syndrome. However, capsaicin may affect its properties, although the underlying mechanisms remain unknown. This study aimed to investigate the effects of dihydrocapsaicin (DHC) on the pharmacokinetics of EFV both in vivo and in vitro. Twelve Sprague–Dawley rats were divided into two groups including experimental and control. The experimental group was pretreated with DHC (10 mg/kg/day) for two weeks with 5% sodium carboxymethyl cellulose prior to receiving EFV. After a single-dose oral administration of 56 mg/kg EFV, blood samples (50 μL) were collected from the caudal vein and analyzed. The effects of DHC on EFV in vitro were further studied in rat liver microsomes (RLMs). The area under the plasma concentration–time curve for EFV increased from 8821.45 ± 2877.31 to 22347.15 ± 7579.96 μg/mL/h ( p < 0.05); the maximum plasma time increased from 2.50 ± 0.84 to 3.50 ± 0.55 h ( p < 0.05) and elimination half-life increased from 3.13 ± 0.87 to 3.51 ± 0.79 h ( p < 0.05). In contrast, the plasma clearance rate decreased from 6.71 ± 2.48 to 2.65 ± 0.98 L/h/kg ( p < 0.05) in the experimental group compared to that in the control group. Additionally, the results showed that DHC significantly inhibited the metabolism of EFV in RLMs. Drug–drug interactions were observed between DHC and EFV, altering the pharmacokinetics of EFV both in vivo and in vitro. The dosage of capsaicin should be monitored and adjusted in patients receiving EFV maintenance therapy.
研究领域:
药理学
·
药物代谢
·
毒理学
·
体外与体内研究
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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）