Transepithelial transport mechanisms of 7,8-dihydroxyflavone, a small molecular TrkB receptor agonist, in human intestinal Caco-2 cells

Chen, Yufeng; Xia, Guobin; Zhao, Zhenlei; Chen, Chun; Li, Yunhong; Zhang, Ying

doi:10.1039/c9fo01007f

Cited by 21 publications

(14 citation statements)

References 60 publications

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“…Therefore, optimization of the chemical structure of 7,8-DHF or development of its analogues might exhibit a positive dose-dependent effect, extending the inhibitory activity for osteoclastogenesis. Zhang et al, 2019). One of the possible causes of their dual effects might result from that they can target multiple signaling pathways and display various beneficial pharmacologic effects (Jiang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…7,8-DHF has been identified as a promising small-molecular BDNF mimetic compound, which mimics the physiological actions of BDNF via directly binding to the extracellular domain of TrkB to trigger TrkB receptor dimerization and autophosphorylation ( Jang et al, 2010 ). 7,8-DHF has been broadly validated in various BDNF-implicated disease models including a variety of neurological diseases, mental diseases, metabolic diseases, and obesity ( Agrawal et al, 2015 ; Bollen et al, 2012 ; Chen et al, 2019 ; Liu et al, 2016b ; Pandey et al, 2020 ; Zhang et al, 2014 ). Especially, 7,8-DHF displays robust therapeutic efficacy toward Alzheimer’s disease (AD) ( Gao et al, 2016 ; Zhang et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

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7,8-Dihydroxyflavone modulates bone formation and resorption and ameliorates ovariectomy-induced osteoporosis

Zhao

Han

et al. 2021

eLife

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Imbalances in bone formation and resorption cause osteoporosis. Mounting evidence supports that brain-derived neurotrophic factor (BDNF) implicates in this process. 7,8-dihydroxyflavone (7,8-DHF), a plant-derived small molecular TrkB agonist, mimics the functions of BDNF. We show that both BDNF and 7,8-DHF promoted the proliferation, osteogenic differentiation and mineralization of MC3T3-E1 cells. These effects might be attributed to the activation of the Wnt/β-catenin signaling pathway as the expression of cyclin D1, phosphorylated-glycogen synthase kinase-3β (p-GSK3β), β-catenin, Runx2, Osterix and osteoprotegerin (OPG) were all significantly up-regulated. Knockdown of β-catenin restrained the up-regulation of Runx2 and Osterix stimulated by 7,8-DHF. In particular, blocking TrkB by its specific inhibitor K252a suppressed 7,8-DHF-induced osteoblastic proliferation, differentiation and expression of osteoblastogenic genes. Moreover, BDNF and 7,8-DHF repressed osteoclastic differentiation of RAW264.7 cells. The transcription factor c-fos and osteoclastic genes such as tartrate-resistant acid phosphatase (TRAP), matrix metalloprotein-9 (MMP-9), Adamts5 were inhibited by 7,8-DHF. More importantly, 7,8-DHF attenuated bone loss, improved trabecular microarchitecture, tibial biomechanical properties and bone biochemical indexes in an ovariectomy (OVX) rat model. The current work highlights the dual regulatory effects that 7,8-DHF exerts on bone remodeling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

7,8-Dihydroxyflavone modulates bone formation and resorption and ameliorates ovariectomy-induced osteoporosis

Zhao

Han

et al. 2021

eLife

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“…Pancreatin (4 × USP specification) and zein (≥95%) and was purchased from Sigma-Aldrich (MO, USA). Dextran (10,40, and 70 kDa) and kaempferol (>98%) and was received from Aladdin Co., Ltd. (Shanghai, China). Pepsin (activity 3,000-3,500 U/mg) and bile salts and were obtained from Sangon Biotech Co., Ltd. (Shanghai, China).…”

Section: Materials and Chemicalsmentioning

confidence: 99%

“…However, methylation, sulfation, and glucuronidation of 7,8-DHF in the intestinal tract and liver caused its extremely low oral bioavailability ( 9 ). In our previous research, we testified that the permeability coefficient of 7,8-DHF was lower than 3 × 10 −6 cm/s, and it had an active efflux mediated by multidrug resistance-related proteins (MRPs, especially MRP 2 outflow) and P-glycoprotein (P-gp) ( 10 ). Thus, the low chemical instability, low oral bioavailability, and high intestinal efflux of 7,8-DHF restricted its application as a functional component in the food industry.…”

Section: Introductionmentioning

confidence: 99%

Establishment and Characterization of Stable Zein/Glycosylated Lactoferrin Nanoparticles to Enhance the Storage Stability and in vitro Bioaccessibility of 7,8-Dihydroxyflavone

et al. 2022

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In this work, the lactoferrin (LF) was glycosylated by dextran (molecular weight 10, 40, and 70 kDa, LF 10K, LF 40K, and LF 70K) via Maillard reaction as a stabilizer to establish zein/glycosylated LF nanoparticles and encapsulate 7,8-dihydroxyflavone (7,8-DHF). Three zein/glycosylated LF nanoparticles (79.27–87.24 nm) with low turbidity (<0.220) and polydispersity index (PDI) (<0.230) were successfully established by hydrophobic interactions and hydrogen bonding. Compared with zein/LF nanoparticles, zein/glycosylated LF nanoparticles further increased stability to ionic strength (0–500 mM NaCl) at low pH conditions. Zein/glycosylated LF nanoparticles had nanoscale spherical shape and glycosylated LF changed surface morphology of zein nanoparticles. Besides, encapsulated 7,8-DHF exhibited an amorphous state inside zein/glycosylated LF nanoparticles. Most importantly, zein/glycosylated LF nanoparticles had good water redispersibility, high encapsulation efficiency (above 98.50%), favorable storage stability, and bioaccessibility for 7,8-DHF, particularly LF 40K. Collectively, the above research provides a theoretical reference for the application of zein-based delivery systems.

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“…However, glucuronidation, sulfation, and methylation of Foods 2021, 10, 2629 2 of 21 7,8-DHF in the intestinal tract or liver caused its extremely low oral bioavailability [9]. In our previous study, we testified that 7,8-DHF's permeability coefficient was lower than 3 × 10 −6 cm/s and had an active efflux mediated by multidrug resistance-related proteins (MRPs, especially MRP 2 outflow) and P-glycoprotein (P-gp) [10]. Thus, the low chemical instability, poor water solubility, and intestinal efflux of 7,8-DHF limit its application as a nutraceutical ingredient in functional food and beverage products.…”

Section: Introductionmentioning

confidence: 99%

Development, Characterization, Stability and Bioaccessibility Improvement of 7,8-Dihydroxyflavone Loaded Zein/Sophorolipid/Polysaccharide Ternary Nanoparticles: Comparison of Sodium Alginate and Sodium Carboxymethyl Cellulose

Chen

Peng

Wang

et al. 2021

Foods

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In this study, two polysaccharides [sodium alginate (ALG) and sodium carboxymethyl cellulose (CMC)] were selected to establish zein/sophorolipid/ALG (ALG/S/Z) and zein/sophorolipid/ALG (CMC/S/Z) nanoparticles to encapsulate 7,8-dihydroxyflavone (7,8-DHF), respectively. The results showed that polysaccharide types significantly affected performance of ternary nanoparticles, including CMC/S/Z possessed lower polydispersity index, particle size and turbidity, but higher zeta potential, encapsulation efficiency and loading capacity compared to ALG/S/Z. Compared to zein/sophorolipid nanoparticles (S/Z), both ALG/S/Z and CMC/S/Z had better stability against low pH (pH 3~4) and high ionic strengths (150~200 mM NaCl). Hydrophobic effects, electrostatic interactions and hydrogen bonding were confirmed in ternary nanoparticles fabrication via Fourier-transform infrared spectroscopy. Circular dichroism revealed that CMC and ALG had no evident impact on secondary structure of zein in S/Z, but changed surface morphology of S/Z as observed by scanning electron microscope. Encapsulated 7,8-DHF exhibited an amorphous state in ternary nanoparticles as detected by X-ray diffraction and differential scanning calorimetry. Furthermore, compared to S/Z, ALG/S/Z, and CMC/S/Z remarkably improved the storage stability and bioaccessibility of 7,8-DHF. CMC/S/Z possessed a greater storage stability for 7,8-DHF, however, ALG/S/Z exhibited a better in vitro bioaccessibility of 7,8-DHF. This research provides a theoretical reference for zein-based delivery system application.

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Transepithelial transport mechanisms of 7,8-dihydroxyflavone, a small molecular TrkB receptor agonist, in human intestinal Caco-2 cells

Abstract: 7,8-DHF was transported across Caco-2 cell monolayers by passive transport with carrier-mediated influx and efflux transporters.

Cited by 21 publications

References 60 publications

7,8-Dihydroxyflavone modulates bone formation and resorption and ameliorates ovariectomy-induced osteoporosis

7,8-Dihydroxyflavone modulates bone formation and resorption and ameliorates ovariectomy-induced osteoporosis

Establishment and Characterization of Stable Zein/Glycosylated Lactoferrin Nanoparticles to Enhance the Storage Stability and in vitro Bioaccessibility of 7,8-Dihydroxyflavone

Development, Characterization, Stability and Bioaccessibility Improvement of 7,8-Dihydroxyflavone Loaded Zein/Sophorolipid/Polysaccharide Ternary Nanoparticles: Comparison of Sodium Alginate and Sodium Carboxymethyl Cellulose

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