INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2018
·
IF 3.862
Wenhui Tao,Dongyang Zhao,Mengchi Sun,Ziyu Wang,Bin Lin,Yu Bao,Yingying Li,Zhonggui He,Yinghua Sun,Jin Sun
Decitabine (DAC), a potent DNA methyltransferase (DNMT) inhibitor, has a limited oral bioavailability. Its 5′-amino acid ester prodrugs could improve its oral delivery but the specific absorption mechanism is not yet fully understood. The aim of this present study was to investigate the in vivo absorption and activation mechanism of these prodrugs using in situ intestinal perfusion and pharmacokinetics studies in rats. Although PEPT1 transporter is pH dependent, there appeared to be no proton cotransport in the perfusion experiment with a preferable transport at pH 7.4 rather than pH 6.5. This suggested that the transport was mostly dependent on the dissociated state of the prodrugs and the proton gradient might play only a limited role. In pH 7.4 HEPES buffer, an increase in P eff was observed for L-val-DAC, D-val-DAC, L-phe-DAC and L-trp-DAC (2.89-fold, 1.2-fold, 2.73-fold, and 1.90-fold, respectively), compared with the parent drug. When co-perfusing the prodrug with Glysar, a known substrate of PEPT1, the permeabilities of the prodrugs were significantly inhibited compared with the control. To further investigate the absorption of the prodrugs, L-val-DAC was selected and found to be concentration-dependent and saturable, suggesting a carrier-mediated process (intrinsic K m : 7.80 ± 2.61 mM) along with passive transport. Determination of drug in intestinal homogenate after perfusion further confirmed that the metabolic activation mainly involved an intestinal first-pass effect. In a pharmacokinetic evaluation, the oral bioavailability of L-val-DAC, L-phe-DAC and L-trp-DAC were nearly 1.74-fold, 1.69-fold and 1.49-fold greater than that of DAC. The differences in membrane permeability and oral bioavailability might be due to the different stability in the intestinal lumen and the distinct PEPT1 affinity which is mainly caused by the stereochemistry, hydrophobicity and steric hindrance of the side chains. In summary, the detailed investigation of the absorption mechanism by in vivo intestinal perfusion and pharmacokinetic studies showed that the prodrugs of DAC exhibited excellent permeability and oral bioavailability, which might be attributed to a hybrid (partly PEPT1-mediated and partly passive) transport mode and a rapid activation process in enterocytes.
研究领域:
药理学
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药物代谢动力学
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分子生物学
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DOI
PubMed
高影响因子
DRUG DELIVERY
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2018
·
IF 3.095
Yuqian Du,Chutong Tian,Menglin Wang,Di Huang,Wei Wei,Yan Liu,Lin Li,Bingjun Sun,Longfa Kou,Qiming Kan,Kexin Liu,Cong Luo,Jin Sun,Zhonggui He
Oligopeptide transporter 1 (PepT1) has been a striking prodrug-designing target. However, the underlying mechanism of PepT1 as a target to facilitate the oral absorption of nanoparticles (NPs) remains unclear. Herein, we modify Poly (lactic-co-glycolic acid) (PLGA) NPs with the conjugates of dipeptides (L-valine-valine, L-valine-phenylalanine) and polyoxyethylene (PEG Mw: 1000, 2000) stearate to facilitate oral delivery of docetaxel (DTX) to investigate the oral absorption mechanism and regulatory effects on PepT1 of the dipeptide-modified NPs. The cellular uptake of the dipeptide-modified NPs is more efficient than that of the unmodified NPs in the stably transfected hPepT1- Hela cells and Caco-2 cells, suggesting the involvement of PepT1 in the endocytosis of NPs. The internalization of the dipeptide-modified NPs is proved to be a proton-dependent process. Moreover, the L-valine-valine modified NPs with shorter PEG chain exhibit distinct advantages in terms of intestinal permeability and oral absorption, resulting in significantly improved oral bioavailability of DTX. In summary, PepT1 could serve as a desirable target for oral nanoparticulate drug delivery and the dipeptide-modified NPs represent a promising nanoplatform to facilitate oral delivery of hydrophobic drugs with low bioavailability.
研究领域:
药剂学
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纳米医学
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药物递送系统
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DOI
PubMed
高影响因子
Biomaterials Science
·
2019
·Vol. 7
·期 10
·4299-4309
·
IF 5.251
Ya Wu,Minghui Sun,Dan Wang,Genyun Li,Jiangeng Huang,Songwei Tan,Lin Bao,Qian Li,Gao Li,Luqin Si
To effectively alleviate acute severe ulcerative colitis (ASUC), we developed a colon-specific delivery system—PLGA–KPV/MMT/CS multifunctional medicinal nanoparticles loaded with cyclosporine A (CyA). The lysine–proline–valine (KPV) tripeptide, which possesses anti-inflammatory properties and high affinity to peptide transporter 1 (PepT1), can target therapy-related cells (colonic epithelial cells and macrophages) via overexpression of PepT1. Montmorillonite (MMT)/chitosan (CS) coating can reduce CyA leakage in the upper gastrointestinal tract (GIT) and enhance nanoparticle adhesion to the inflamed colon. The bio-distribution demonstrated that nanoparticles can specifically accumulate in the inflamed tissues and can be retained for up to 36 h. After being treated with the CyA–PLGA–KPV/MMT/CS nanoparticles (PKMCN), the mice with DSS-induced ulcerative colitis exhibited significant improvements in body weight, colon length, and disease activity index. Moreover, biochemistry and immunohistochemical analysis showed that the PKMCN treatment group performed as well as the healthy group. Intriguingly, PKMCN without CyA also presented marked therapeutic effects. Our results suggested that PKMCN could be a promising drug delivery system for ASUC therapy by targeting inflamed cells, prolonging curative time, and mitigating colitis.
研究领域:
药学
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胃肠病学
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纳米医学
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炎症性肠病
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产品关联
DOI
PubMed
高影响因子
FOOD RESEARCH INTERNATIONAL
·
2026
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IF 8.8
Xiaowang Wang,Ge Xu,Lingyun Gu,Yue Hong,Zhipeng Yu,Wenzhu Zhao
Apical-out organoids enable direct FGR-PepT1 contact, overcoming model limitations. • FGR activates three pathways remodeling apical niche for PepT1 self-enhancement. • Proteomics reveals self-enhanced absorption mechanism of egg-white tripeptide FGR. Our previous study has verified efficient PepT1-mediated transport of the egg white-derived tripeptide FGR (Phe-Gly-Arg), but its transport mechanism under physiological intestinal conditions remains elusive and is difficult to fully recapitulate using conventional culture models. This study established an apical-out mouse jejunal organoid model combined with Astral-DIA quantitative proteomics to investigate the molecular mechanisms and regulatory factors underlying egg white-derived tripeptide FGR transport via PepT1. Immunofluorescence confirmed that the model achieved successful polarity reversal, exposed the apical brush border, maintained the integrity of the F-actin cytoskeleton, tight junctions, and adherens junctions, and preserved normal intestinal epithelial cell lineages including absorptive cells and Paneth cells. After 4 h of apical-side FGR exposure, 682 differentially expressed proteins were identified, which were mainly enriched in the apical plasma membrane, microvillar structures, cytoskeleton remodeling, and nutrient-sensing pathways. KEGG analysis showed that glucagon signaling, PPAR signaling, and tight junction pathways were significantly activated, with key proteins such as GCG, ACOX2, EZR, and VASP markedly upregulated. These results demonstrate that FGR acts as a nutrient signal to trigger multi-dimensional epithelial adaptation and optimize the PepT1 transport microenvironment by regulating nutrient sensing, lipid-energy metabolism, and apical cytoskeleton remodeling, thereby modulating the molecular process of FGR transport via PepT1. This study provides proteomic evidence for the transport mechanism of food-derived peptides targeting PepT1. Download: Download high-res image (196KB) Download: Download full-size image
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DOI
高影响因子
Pharmaceutics
·
2022
·Vol. 14
·期 6
·1277
·
IF 6.525
Huimin Wu,Yuchen Xu,Mengru Cai,Longtai You,Jing Liu,Xiaoxv Dong,Xingbin Yin,Jian Ni,Changhai Qu
The incidence of ocular surface disease (OSD) is increasing, with a trend towards younger ages. However, it is difficult for drugs to reach the deep layers of the cornea due to ocular surface barriers, and bioavailability is less than 5%. In this study, DSPE-PEG2000 was modified with L-valine (L-Val), and an HS15/DSPE-PEG2000-L-Val nanomicelle delivery system containing baicalin (BC) ([email protected]/DSPE-PEG2000-L-Val) was constructed using thin-film hydration, with a high encapsulation rate, small particle size and no irritation to the ocular surface. Retention experiments on the ocular surface of rabbits and an in vivo corneal permeation test showed that, compared with the control, nanomicelles not only prolonged retention time but also enhanced the ability to deliver drugs to the deep layers of the cornea. The results of a protein inhibition and protein expression assay showed that nanomicelles could increase uptake in human corneal epithelial cells (HCEC) through energy-dependent endocytosis mediated by clathrin, caveolin and the carrier pathway mediated by PepT1 by inhibiting the overexpression of claudin-1 and ZO-1 and suppressing the expression of PepT1-induced by drug stimulation. These results indicate that[email protected]/DSPE-PEG2000-L-Val is suitable for drug delivery to the deep layers of the ocular surface, providing a potential approach for the development of ocular drug delivery systems.Keywords:L-valine;nanomicelles;baicalin;PepT1;endocytosis proteins;tight junction proteins;ocular drug delivery system
研究领域:
药学
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眼科学
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纳米技术
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药物递送系统
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DOI
PubMed
高影响因子
FOOD RESEARCH INTERNATIONAL
·
2024
·
IF 7
Yu Xiao,Zeyun Zhao,Tao Zhang,Xiaoqi Xu,Anik Khan,Yibin Qiu,Zheng Xu,Sha Li,Hong Xu
Pigeon egg white (PEW) is widely recognized as a promising source of bioactive proteins, with a high degree of glycosylation. This study focused on the characterization of a novel glycoprotein extracted from PEW, known as ovalbumin-related protein Y (OVAY). Our investigation included an analysis of the N-glycan and protein structures of OVAY, as well as an examination of simulated gastrointestinal digestive products and the transmembrane transport mechanism of OVAY-digested peptides. The results revealed that OVAY contains two glycosylation sites (Asn 62, 215) and consists of 30 N-linked glycoforms, with the top three glycans being N6H3, N6H7S1, and N6H5. Additionally, OVAY is rich in Gal and sialic acid and exhibits a rod-like molecular structure. Furthermore, it was found that OVAY demonstrates resistance to gastric digestion, with its digested peptides primarily transported via PepT1 and endocytosis. This study provides insight into the glycoprotein structure of OVAY and elucidates its physiological activity, providing a theoretical reference for the development of a novel sialate-rich protein.
研究领域:
生物化学
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蛋白质科学
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食品科学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2022
·
IF 16.744
Ruijie Chen,Xinlu Lin,Qian Wang,Xingsi An,Xinyu Zhao,Yujie Lin,Tuyue Sun,Chenyang Yan,Aimin Cai,Weilan Cao,Youting Zhang,Qing Yao,Longfa Kou
Ulcerative colitis (UC) is a chronic recurrent disease of the gastrointestinal tract. Though the exact etiology is still unknown, inflamed enterocytes, activated macrophages, and the crosstalk between them have been widely believed to play vital roles in the UC progression. Therefore, simultaneously modulating both injured intestinal epithelial cells and activated immune cells could effectively normalize the intestinal microenvironment by regulating cell-specific activities and breaking the vicious loop between them. Herein, we designed a PepT1 and CD44 dual-targeted celecoxib nanoparticle ( [email protected] ) that could selectively deliver celecoxib to both the inflamed enterocytes and the activated M1 macrophages for UC treatment. [email protected] exhibited excellent cell-specific targeting ability to both inflamed epitheliums and M1 macrophages. In vitro studies showed that [email protected] could exert an enhanced anti-inflammatory effect and improve the colonic inflammatory microenvironment via directly modulating Nrf2/HO-1 and NF-κB pathways in epithelial cells and promoting M1 to M2 macrophage polarization. In a DSS-induced mice model, [email protected] significantly attenuated bodyweight loss, reduced colon length shortening, lowered the disease activity index score and alleviated colon histological damage. In addition, [email protected] could also regulate the intestinal flora in UC mice toward a healthier state with improved species uniformity and abundance as well as restored species diversity. Notably, both in vivo and in vitro data proved that [email protected] had more robust therapeutic activity than both Cel solution and single targeted nanoparticle. This study provides a potential strategy for UC drug delivery and effective treatment.
研究领域:
药学
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生物医学工程
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免疫学
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胃肠病学
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产品关联
DOI
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Siyi Wang,Ximing Yang,Shuzhen Cheng,Ming Du
Zinc is an essential mineral for human health, and its deficiency can lead to various health issues. Oysters ( Crassostrea gigas ) are known to be a rich source of protein-bound zinc. Oyster peptides were complexed with zinc sulfate (ZnSO 4 ) to be oyster peptide-zinc chelates (OPZs) that offer potential as a valuable zinc supplement. The complexation of zinc with oyster peptides induces conformational changes in the peptides, altering their overall spatial arrangement. This could potentially impact their functions and properties. OPZs have demonstrated enhanced physical and gastrointestinal stability, as they are resistant to digestion by pepsin and trypsin. The research has shown that OPZs can modulate the expression of key proteins involved in zinc binding (MT1), peptide transport (PePT1), and zinc transport (ZIP4 and ZnT1) in enterocytes. By regulating the proteins expression, OPZs have the potential to affect zinc absorption and homeostasis. Furthermore, OPZs have been found to enhance zinc absorption through dual pathways compared to the single pathway of inorganic zinc. Additionally, they have the potential to improve zinc bioaccessibility and bioavailability, meaning they can make zinc more easily absorbed by the body and readily available for use.
研究领域:
营养学
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生物化学
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分子生物学
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食品科学
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产品关联
DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Sijia Wu,Ping Jiang,Xiaoliang Zhang,Chen Mao,Yaxi Dai,Hong Zhuang,Yong Pang
Understanding the transport mechanism of the peptide Asn-Cys-Trp (NCW) is crucial to improving its intestinal absorption and bioavailability. This study investigated the absorption of NCW through Caco-2 cell monolayers and its interaction with the DPPC bilayers. Results revealed that after a 3 h incubation, the Papp (AP-BL) and Papp (BL-AP) values of NCW at a concentration of 5 mmol/L were (22.24 ± 4.52) × 10–7 and (6.63 ± 2.31) × 10–7 cm/s, respectively, with the transport rates of 1.59 ± 0.32 and 0.62 ± 0.20%, indicating its moderate absorption. NCW was found to be transported via PepT1 and paracellular transport pathways, as evidenced by the significant impact of Gly-Pro and cytochalasin D on the Papp values. Moreover, NCW upregulated ZO-1 mRNA expression. Further investigation of the ZO-1-mediated interaction between NCW and tight junction proteins will contribute to a better understanding of the paracellular transport mechanism of NCW. The interaction between NCW and the DPPC bilayers was predominantly driven by entropy. NCW permeated the bilayers through electrostatic, hydrogen bonding, and hydrophobic interactions, resulting in increased fluidity, flexibility, and disorder as well as phase transition and phase separation of the bilayers.
研究领域:
药理学
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生物物理学
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细胞生物学
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膜科学
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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）