Materials Today Bio
·
2024
·
IF 8.7
Gong Li,Lu Han,Li-Juan Xia,Ang Gao,Zhi-Peng Li,Shi-Ying Zhou,Lei Wan,Yao Deng,Tian-Hong Zhou,Xin-Yi Lu,Yang Luo,Dun-Sheng Liang,Gui-Ting Wu,Sheng-Qiu Tang,Xin-Lei Lian,Hao Ren,Xiao-Ping Liao,Liang Chen,Jian Sun
Plasmid-mediated conjugative transfer of antibiotic resistance genes (ARGs) within the human and animal intestine represents a substantial global health concern. linoleic acid (LA) has shown promise in inhibiting conjugation in vitro , but its in vivo effectiveness in the mammalian intestinal tract is constrained by challenges in efficiently reaching the target site. Recent advancements have led to the development of waterborne polyurethane nanoparticles for improved drug delivery. In this study, we synthesized four waterborne polyurethane nanoparticles incorporating LA (WPU@LA) using primary raw materials, including N-methyldiethanolamine, 2,2'-(piperazine-1,4-diyl) diethanol, isophorone diisocyanate, castor oil, and acetic acid. These nanoparticles, identified as WPU 0.89 @LA, WPU 0.99 @LA, WPU 1.09 @LA, and WPU 1.19 @LA, underwent assessment for their pH-responsive release property and biocompatibility. Among these, WPU 0.99 @LA displayed superior pH-responsive release properties and biocompatibility towards Caco-2 and IPEC-J2 cells. In a mouse model, a dosage of 10 mg/kg/day WPU 0.99 @LA effectively reduced the conjugation of IncX4 plasmids carrying the mobile colistin resistance gene ( mcr-1 ) by more than 45.1-fold. In vivo toxicity assessment demonstrated that 10 mg/kg/day WPU 0.99 @LA maintains desirable biosafety and effectively preserves gut microbiota homeostasis. In conclusion, our study provides crucial proof-of-concept support, demonstrating that WPU 0.99 @LA holds significant potential in controlling the spread of antibiotic resistance within the mammalian intestine.
研究领域:
药理学
·
纳米技术
·
微生物学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
·
2024
·
IF 2.6
Yun Meng,Ye Cai,Mengyao Cui,Yuhang Xu,Long Wu,Xiang Li,Xiaoqin Chu
The aim of this study was to prepare a solid self-microemulsifying drug delivery system (S-SMEDDS) of cinnamaldehyde (CA) by spray drying technique to improve the oral bioavailability of CA. The preparation of CA S-SMEDDS with maltodextrin as the solid carrier, a core-wall material mass ratio of 1:1, a solid content of 20% (w/v), an inlet air temperature of 150 °C, an injection speed of 5.2 mL/min, and an atomization pressure of 0.1 MPa was determined by using the encapsulation rate as the index of investigation. Differential scanning calorimetry (DSC) revealed the possibility of CA being encapsulated in S-SMEDDS in an amorphous form. The in-vitro release showed that the total amount of CA released by S-SMEDDS was approximately 1.3 times higher than that of the CA suspension. Pharmacokinetic results showed that the relative oral bioavailability of CA S-SMEDDS was also increased to 1.6-fold compared to CA suspension. Additionally, we explored the mechanism of CA uptake and transport of lipid-soluble drugs CA by S-SMEDDS in a Caco-2/HT29 cell co-culture system for the first time. The results showed that CA S-SMEDDS uptake on the co-culture model was mainly an energy-dependent endocytosis mechanism, including lattice protein-mediated endocytosis and vesicle-mediated endocytosis. Transport experiments showed that CA S-SMEDDS significantly increased the permeability of CA in this model. These findings suggested that CA S-SMEDDS is an effective oral solid dosage form for increasing the oral bioavailability of lipid-soluble drug CA.
研究领域:
药剂学
·
药物递送系统
·
药代动力学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Sisi Yi,Tao Guo,Yan Wang,Xiaodi Yang,Yue Liao,Xiyu Tang,Xiangjun Zhang
A novel micrometer-sized porous cyclodextrin polymer (PCDP) was synthesized through the cross-linking of carboxymethyl β-cyclodextrin with 1,6-diaminohexane. We hypothesized that PCDP could be utilized as a drug carrier to enhance the dissolution rate and oral bioavailability of poorly soluble drugs. Ibuprofen (IBU), selected as the model poorly soluble drug, was successfully loaded into PCDP, resulting in a significant improvement in IBU release within simulated gastric fluid. Compared to IBU alone, IBU-loaded PCDP markedly increased the oral bioavailability of IBU, with an approximately 4-fold increase in the area under the curve (AUC) and a 3-fold increase in C max , thereby enhancing the anti-inflammatory effects in rat models. Additionally, PCDP demonstrated good biocompatibility with Caco-2 cells. These findings suggest that the micrometer sized PCDP may be a promising drug carrier for improving the dissolution and oral bioavailability of poorly soluble drugs.
研究领域:
药学
·
药物递送系统
·
药物动力学
·
生物药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2020
·
IF 7.727
Yajie Yin,Hailiang Deng,Kai Wu,Bing He,Wenbing Dai,Hua Zhang,Jijun Fu,Yuan Le,Xueqing Wang,Qiang Zhang
Nanotechniques show significant merits in terms of improving the oral bioavailability of poorly water-soluble drugs. However, the mechanisms behind are not clear yet. For instance, what is the contribution of free drug released during nanogranule transcytosis , as well as the impact of drug transporter and chylomicron ? To address these issues, sorafenib nanogranules (SFN-NGs) were prepared as model by the high-gravity antisolvent precipitation method which approaches to practical mass production. Then, a multiaspect study on the transcytosis mechanism of SFN-NGs was conducted in Caco-2 cells and rats, including paracellular transport , endocytosis, intracellular trafficking, transmembrane pathway, as well as the involvement of transporter and chylomicron. Pharmacokinetics in rats demonstrated an obvious superiority of SFN-NGs in oral absorption and lymphatic transfer over SFN crude drugs . Different from free SFN, SFN-NGs could be internalized in cells in early stage by caveolin/lipid raft or clathrin induced endocytosis, and transported intactly through the polarized cell monolayers. While in late stage, transporter-mediated transport of free SFN began to play a vital role on the transmembrane of SFN-NGs. No paracellular transport of SFN-NGs was found, and the trafficking of SFN-NGs was affected by the pathway of ER-Golgi complexes. Surprisedly, the intracellular free SFN was the main source of transmembrane for SFN-NGs, which was entrapped into chylomicrons and then secreted into the extracellular space. Generally, the findings in current study may shed light on the absorption mechanism of oral nanoformulations.
研究领域:
药学
·
纳米技术
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Iranian Journal of Basic Medical Sciences
·
2019
·
IF 1.854
Yan Yan,Fengling Ren,Pengchong Wang,Ying Sun,Jianfeng Xing
Objective(s): This study is aimed to design and synthesize a prodrug of 5-aminosalicylic acid and evaluate its ameliorative effect on experimental ulcerative colitis (UC). Materials and Methods: 5-Aminosalicylic acid-alanine (5-ASA-ALA) was synthesized and characterized. Its stability study was conducted in rat plasma and in the gastrointestinal tract environment, its transport characteristic was assessed using the Caco-2 cells. Its colon-targeting property was evaluated by the pharmacokinetic study, and incubation studies. A series of indicators were used to investigate its therapeutic effect on experimental colitis, including the survival rate and body weight of mice, the disease activity index (DAI), the colonic damage score and colon index, the myeloperoxidase (MPO) activity and the levels of malondialdehyde (MDA), total superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-Px) in colonic tissues. Results: 5-ASA-ALA was barely absorbed in the Caco-2 monolayer or into the rat blood. It was remarkably stable when incubated in the upper gastrointestinal tract, while gradually hydrolyzed in the colon of rats. When orally administered to mice, 5-ASA-ALA had significantly greater therapeutic effect on colitis than the positive control. Conclusion: 5-ASA-ALA is demonstrated to be a promising oral colon-targeting prodrug of 5-ASA and has potential application in UC treatment.
研究领域:
药物学
·
胃肠病学
·
药物开发
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2017
·
IF 3.756
Yixian Liu,Bingjie Liu,Yan Zhang,Youmei Peng,Chenzheng Huang,Ning Wang,Jinhua Jiang,Qingduan Wang,Junbiao Chang
2′-Deoxy-2′-β-fluoro-4′-azidocytidine (FNC), a cytidine analog, has attracted great interest because of its potent activity against wild-type and multidrug-resistant HIV. The purpose of current study was to investigate the absorption mechanisms of FNC in the small intestine, as well as the interactions between FNC and P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). The experiments were performed using Caco-2 cells and the rat small intestine. The uptake experiment indicated that FNC concentration, extracellular pH and the incubated temperature could influence the uptake of FNC in Caco-2 cells. NaN 3 , verapamil , probenecid , MK571 and GF120918 could significantly increase the FNC uptake in Caco-2 cells. The transport experiment showed that both the absorption and secretion of FNC were concentration dependent. The secretion of FNC was approximately 2-fold greater than the absorption. In the presence of verapamil, probenecid, MK571 or GF120918, the efflux ratio decreased by > 50%. In everted rat intestine, the absorption of FNC also depended on its concentration and was not significantly different in the different segments of the small intestine. Real-time RT-PCR results indicated that the gene expressions of P-gp, MRP2 and BCRP were up-regulated after exposure to FNC. The reduction in accumulation of rhodamine 123 after treatment with FNC revealed its ability to up-regulate P-gp activity. In conclusion, FNC was completely absorbed by passive diffusion and active transport mechanisms. P-gp, MRP2 and BCRP could influence the absorption of FNC in the small intestine. FNC could modulate the gene expressions of P-gp, MRP2 and BCRP, and increase the activity of P-gp.
研究领域:
药理学
·
艾滋病治疗
·
药物转运
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Rong Wang,Bowen Yan,Yourui Yin,Xueyuan Wang,Mei Wu,Tiantian Wen,Yin Qian,Yong Wang,Caoxing Huang,Yongqiang Zhu
Pest management technology has been a promising bioconversion method for waste resource utilization. Unlike many pests that consume waste, the larvae of Lucilia sericata , also known as maggots, have many outstanding advantages as following: with their strong adaption to environment and not easily infected and exhibiting a medicinal nutritional value. Herein, the potential efficacies of maggot polysaccharides (MP), as well as their underlying mechanisms, were explored in Dextran sulfate sodium (DSS)-induced colitis mice and TNF-α-elicited Caco-2 cells. We extracted two bioactive polysaccharides from maggots, MP-80 and MP-L, whose molecular weights were 4.25 × 10 3 and 2.28 × 10 3 g/mol, respectively. MP-80 and MP-L contained nine sugar residues: 1,4-α-Arap, 1,3-β-Galp, 1,4,6-β-Galp, 1,6-α-Glcp, 1-α-Glcp, 1,4-β-Glcp, 1-β-Xylp, 1,2-α-Manp, and 1-β-Manp. We demonstrated that MP-80 and MP-L significantly ameliorated DSS-induced symptoms and histopathological damage. Immuno-analysis revealed that compared with MP-L, MP-80 could better restore intestinal barrier and reduced inflammation by suppressing NLRP3/NF-κB pathways, which might be attributed to its enriched galactose fraction. Moreover, 16S rRNA sequencing revealed that MP-80 and MP-L both improved the dysbiosis and diversity of gut microbiota and acted on multiple microbial functions. Our study sheds new light on the possibility of using maggot polysaccharides as an alternative therapy for colitis.
研究领域:
医学
·
药理学
·
微生物学
·
营养学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2020
·
IF 8.579
Mengmeng Qin,Jian Zhang,Minghui Li,Dan Yang,Dechun Liu,Siyang Song,Jijun Fu,Hua Zhang,Wenbing Dai,Xueqing Wang,Yiguang Wang,Bing He,Qiang Zhang
The merits of nanomedicines are significantly impacted by the surrounding biological environment. Similar to the protein corona generated on the surface of nanoparticles in the circulation system, the intracellular protein corona (IPC) might be formed on nanoparticles when transported inside the cells. However, little is known currently about the formation of IPC and its possible biological influence. Methods : Caco-2 cells, a classical epithelial cell line, were cultured in Transwell plates to form a monolayer. Gold nanoparticles (AuNPs) were prepared as the model nanomedicine due to their excellent stability. Here we focused on identifying IPC formed on the surface of AuNPs during cell transport. The nanoparticles in the basolateral side of the Caco-2 monolayer were collected and analyzed by multiple techniques to verify IPC formation. High-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics was utilized to analyze the composition of IPC proteins. In particular, we established a dual-filtration strategy to exclude various interference in IPC identification. Based on the subcellular localization of specific IPC proteins, we elicited the nano-trafficking network of AuNPs. The transport pathways of AuNPs identified by proteomic analysis were also verified by various conventional technologies. Finally, we explored the influence of IPC on the uptake and stress response of endothelium. Results : The existence of IPC was demonstrated on the surface of AuNPs, in which 227 proteins were identified. Among them, 40 proteins were finally ascertained as the specific IPC proteins. The subcellular location analysis indicated that these “specific” IPC proteins could back-track the transport pathways of nanoparticles in the epithelial cell monolayer. According to the subcellular distribution of IPC proteins and co-localization, we discovered a new pathway of nanoparticles from endosomes to secretory vesicles which was dominant during the transcytosis. After employing conventional imageology and pharmacology strategies to verify the result of proteomic analysis, we mapped a comprehensive intracellular transport network. Our study also revealed the merits of IPC analysis, which could readily elucidate the molecular mechanisms of transcytosis. Besides, the IPC proteins increased the uptake and stress response of endothelium, which was likely mediated by extracellular matrix and mitochondrion-related IPC proteins. Conclusion : The comprehensive proteomic analysis of IPC enabled tracing of transport pathways in epithelial cells as well as revealing the biological impact of nanoparticles on endothelium.
研究领域:
纳米技术
·
药学
·
细胞生物学
·
蛋白质组学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
RSC Advances
·
2017
·Vol. 7
·期 80
·50430-50440
·
IF 3.108
Yongsheng Chen,Xiang Ma,Xiong Fu,Rian Yan
Adinandra nitida tea (Shiyacha) is a traditional eminent and flourishing tea with a long history in Southeast Asia. However, transformation of phytochemicals of A. nitida tea infusion during in vitro simulated digestions is vague. Herein, we investigated cellular antioxidant and antiproliferative activity of phytochemicals obtained from A. nitida tea infusion subjected to in vitro gastrointestinal conditions. Phenolic, flavonoid, flavonol, and anthocyanin contents found in A. nitida tea infusion were evaluated by normal colorimetric methods. Subsequently, the main compounds were determined by high-performance liquid chromatography. The antioxidant activity was evaluated based on peroxyl radical scavenging capacity (PSC), oxygen radical absorbance capacity (ORAC), and cellular antioxidant activity (CAA). The antiproliferative activity towards Caco-2 cells was determined by the cell methylene blue colorimetric assay. It was found that in simulated gastrointestinal fluids, the contents of phenolics and flavonols increased, whereas the contents of flavonoids and anthocyanins decreased. Moreover, the content of (−)-epigallocatechin and camellianin B increased, whereas that of L-epicatechin, quercitrin, and camellianin A decreased. Furthermore, the oxygen radical scavenging capacity and cellular antioxidant activity values increased, whereas the PSC values decreased. Most importantly, the gastrointestinal fluids of A. nitida tea infusion exhibited a strong antiproliferative activity towards Caco-2 cells and affected caspase 3/9 signaling pathway, and apoptosis induction might serve as the underlying mechanism for this antiproliferative activity. It can be concluded that A. nitida tea infusion may act as a potential intracellular antioxidant and colon cancer cell proliferation inhibitor.
研究领域:
食品科学
·
营养学
·
药理学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Sikai Deng,Weiwei Li,Qiyu Chen,Jianqun Shao,Junbo Zhang,Yuji Wang,Yinghuan Li
The mucus layer and intestine epithelium pose challenges to the bioavailability of orally administered paclitaxel (PTX). A novel P-glycoprotein inhibitor, (S)-2-decanoylamino-3-(1-naphthyl)propionyl-leucyl-valine (PgpI), was synthesized in this study. Its structure was characterized using 1 H NMR, 13 C NMR, ESI-MS and IR spectroscopies. The efficacy and in vivo toxicity of PgpI were comprehensively evaluated by R8-PEG@PLs&PgpI, i.e. , the oral combination of PgpI and octaarginine R8-PEG-DSPE modified PTX liposomes (R8-PEG@PLs), for lung cancer treatment. The joint forms between PgpI and R8-PEG@PLs were investigated and the affinity of PgpI for intestinal P-glycoprotein remained unaffected when combined externally with R8-PEG@PLs (R8-PEG@PLs&PgpI), compared to the diminished affinity for internal combination. The primary endocytic pathway for R8-PEG@PLs&PgpI in Caco-2 cells was the lipid raft, with increased percentage of macropinocytosis compared to unmodified PTX liposomes (PLs). The established physiology-based cellular kinetic models revealed that the net internalization rate of PTX was 2.3 times higher in R8-PEG@PLs&PgpI than in PLs, correlating with in vivo 2.2 times of antitumor rate. R8-PEG@PLs&PgpI may address the deficits of PLs in human lung A549 tumor-bearing mice due to the lower drug concentration than in normal mice. The external combination of R8-PEG@PLs&PgpI, offering maximal efficacy and security of PgpI, is promising for oral PTX delivery.
研究领域:
药学
·
肿瘤学
·
药物递送系统
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
FOOD RESEARCH INTERNATIONAL
·
2024
·
IF 7
Shuqi Hao,Mengyu Ye,Na Li,Zeyu Lu,Wei Quan,Huaide Xu,Mei Li
Advanced glycation end products (AGEs), a heterogeneous compound existed in processed foods, are related to chronic diseases when they are accumulated excessively in human organs. Protein-bound N ε -(carboxymethyl) lysine (CML) as a typical AGE, is widely determined to evaluate AGEs level in foods and in vivo . This study investigated the intestinal absorption of three protein-bound CML originated from main food raw materials (soybean, wheat and peanut). After in vitro gastrointestinal digestion, the three protein-bound CML digests were ultrafiltered and divided into four fractions: less than 1 kDa, between 1 and 3 kDa, between 3 and 5 kDa, greater than 5 kDa. Caco-2 cell monolayer model was further used to evaluate the intestinal absorption of these components. Results showed that the absorption rates of soybean protein isolate (SPI)-, glutenin (Glu)-, peanut protein isolate (PPI)-bound CML were 30.18%, 31.57% and 29.5%, respectively. The absorption rates of components with MW less than 5 kDa accounted for 19.91% (SPI-bound CML), 22.59% (Glu-bound CML), 23.64% (PPI-bound CML), respectively, and these samples were absorbed by paracellular route, transcytosis route and active route via PepT-1. Taken together, these findings demonstrated that all three protein-bound CML digests with different MW can be absorbed in diverse absorption pathways by Caco-2 cell monolayer model. This research provided a theoretical basis for scientific evaluation of digestion and absorption of AGEs in food.
研究领域:
食品科学
·
营养学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Qiao-Lai Wang,Pei-Xi Zhang,Rui Shen,Meng Xu,Liang Han,Xuan Shi,Zi-Rui Zhou,Jing-Yi Yang,Jie-Qing Liu
Ethnopharmacological relevance Arbutin is a naturally occurring glucoside extracted from plants, known for its antioxidant and tyrosinase inhibiting properties. It is widely used in cosmetic and pharmaceutical industries. With in-depth study of arbutin, its application in disease treatment is expanding, presenting promising development prospects. However, reports on the metabolic stability, plasma protein binding rate, and pharmacokinetic properties of arbutin are scarce. Aim of the study The aim of this study is to enrich the data of metabolic stability and pharmacokinetics of arbutin through the early pre-clinical evaluation, thereby providing some experimental basis for advancing arbutin into clinical research. Materials and methods We developed an efficient and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for determining arbutin in plasma. We investigated the metabolic and pharmacokinetic properties of arbutin through in vitro metabolism assay, cytochrome enzymes P450 (CYP450) inhibition studies, plasma protein binding rate analysis, Caco-2 cell permeability tests, and rat pharmacokinetics to understand its in vivo performance. Results In vitro studies show that arbutin is stable, albeit with some species differences. It exhibits low plasma protein binding (35.35 ± 11.03% ∼ 40.25 ± 2.47%), low lipophilicity, low permeability, short half-life (0.42 ± 0.30 h) and high oral bioavailability (65 ± 11.6%). Arbutin is primarily found in the liver and kidneys and is eliminated in the urine. It does not significantly inhibit CYP450 up to 10 μM, suggesting a low potential for drug interactions. Futhermore, preliminary toxicological experiments indicate arbutin's safety, supporting its potential as a therapeutic agent. Conclusion This study provides a comprehensive analysis the drug metabolism and pharmacokinetics (DMPK) of arbutin, enriching our understanding of its metabolism stability and pharmacokinetics properties, It establishes a foundation for further structural optimization, pharmacological studies, and the clinical development of arbutin.
研究领域:
药理学
·
分析化学
·
临床前研究
✓ 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）