Simulated Microgravity Alters P-Glycoprotein Efflux Function and Expression via the Wnt/β-Catenin Signaling Pathway in Rat Intestine and Brain
Abstract
:1. Introduction
2. Results
2.1. Smg Inhibited the Efflux Function and Expression of P-Gp in Rat Intestine and Caco-2 Cells
2.1.1. SMG Inhibited the Efflux Function and Expression of P-Gp in Rat Intestine
2.1.2. 72 h SMG Treatment Inhibited the Efflux Function and Expression of P-Gp in Caco-2 Cells
2.2. SMG Inhibited the Efflux Function and Activated the Expression of P-Gp in Rat Brain and hCMEC/D3 Cells
2.2.1. SMG Inhibited the Efflux Function and Activated the Expression of P-Gp in Rat Brain
2.2.2. 48 and 72 h SMG Treatment Inhibited the Efflux Function and Activated the Expression of P-Gp in hCMEC/D3 Cells
2.3. SMG Down-Regulated P-Gp Expression by Inhibiting the Wnt/β-Catenin Signaling Pathway in Rat Intestine and Caco-2 Cells
2.4. SMG Up-Regulated P-Gp Expression by Activating the Wnt/β-Catenin Signaling Pathway in Rat Brain and hCMEC/D3 Cells
2.5. SMG Promoted the In Vivo Intestinal Absorption and Brain Distribution of AP
3. Discussion
4. Materials and Methods
4.1. Animal Treatment and Sample Collection
4.2. Efflux Function Analysis of P-Gp in Rat Intestine and Brain
4.3. Immunohistochemical Staining
4.4. Cell Culture and SMG Treatment
4.5. Efflux Function Analysis of P-Gp in Caco-2 and hCMEC/D3 Cells
4.6. Western-Blot
4.7. qPCR
4.8. Immunofluorescence
4.9. Rat Single-Pass Intestinal Perfusion of Acetaminophen
4.10. Rat Brain Distribution of Acetaminophen
4.11. Acetaminophen Determination Using the HPLC-UV Method
4.12. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
P-gp | permeability glycoprotein |
MG | microgravity |
SMG | simulated microgravity |
CON | Control |
IECs | intestinal epithelial cells |
BBB | blood-brain barrier |
AP | acetaminophen |
Caco-2 | human colon adenocarcinoma cell |
hCMEC/D3 | human cerebral microvascular endothelial cell |
CsA | cyclosporine A |
Ver | Verapamil |
IHC | immunohistochemical |
qPCR | Quantitative Polymerase Chain Reaction |
rhodamine 123 | Rho123 |
pho-Dvl2 | phosphorylated disheveled 2 |
GSK-3β | glycogen synthase kinase-3β |
DKK1 | Dickkopf 1 |
SPIP | single-pass intestinal perfusion |
Peff | effective permeability |
HPLC | high-performance liquid chromatography |
IS | internal standard |
Ka | absorption constant |
Kp brain | brain-to-plasma concentration ratio |
Axin | axis inhibitor |
APC | adenomatous polyposis coli protein |
CK1 | casein kinase 1 |
Fzd | Frizzled |
LRP5/6 | lipoprotein receptor-related proteins 5/6 |
TCF | transcription factor |
BSA | bovine serum albumin |
TBST | Tris-buffered saline tween |
DMSO | dimethyl sulfoxide |
PBS | phosphate buffer saline |
GAPDH | glyceraldehyde-3-phosphate dehydrogenase |
KR solution | Krebs–Ringer’s solution |
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Concentration (mg/mL) | Ka (10−2, min−1) | Peff (10−3, cm/min) | ||
---|---|---|---|---|
7 days | CON | 1.684 ± 0.015 | 7.75 ± 0.11 | 8.86 ± 0.16 |
CON + Ver | 1.516 ± 0.052 * | 8.93 ± 0.37 * | 10.77 ± 0.61 * | |
SMG | 1.571 ± 0.029 ** | 8.55 ± 0.21 ** | 10.11 ± 0.33 ** | |
21 days | CON | 1.965 ± 0.033 | 5.66 ± 0.19 | 6.01 ± 0.23 |
CON + Ver | 1.727 ± 0.025 ** | 7.44 ± 0.18 ** | 8.41 ± 0.25 ** | |
SMG | 1.54 ± 0.066 ** | 8.76 ± 0.47 ** | 10.47 ± 0.76 ** |
Gene | Primer | Sequences |
---|---|---|
Rat mdr1a | Forward | 5′-GGTTCGGTGCCTACTTGGTG-3′ |
Reverse | 5′-GATGTGGGATGCTGAGACTTTG-3′ | |
Rat mdr1b | Forward | 5′-GAAATAATGCTTATGAATCCCAAA-3′ |
Reverse | 5′-GGTTTCATGGTCGTCGTCTCTTGA-3′ | |
Rat GAPDH | Forward | 5′-TCTCTTGTGACAAAGTGGACAT-3′ |
Reverse | 5′-GGTGATGGGTTTCCCGTTGA-3′ | |
Human MDR1 | Forward | 5′-TTGCTGCTTACATTCAGGTTTCA-3′ |
Reverse | 5′-AGCCTATCTCCTGTCGCATTA-3′ | |
Human GAPDH | Forward | 5′-ACAACTTTGGTATCGTGGAAGG-3′ |
Reverse | 5′-GCCATCACGCCACAGTTTC-3′ |
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Liu, H.; Liang, M.; Deng, Y.; Li, Y. Simulated Microgravity Alters P-Glycoprotein Efflux Function and Expression via the Wnt/β-Catenin Signaling Pathway in Rat Intestine and Brain. Int. J. Mol. Sci. 2023, 24, 5438. https://doi.org/10.3390/ijms24065438
Liu H, Liang M, Deng Y, Li Y. Simulated Microgravity Alters P-Glycoprotein Efflux Function and Expression via the Wnt/β-Catenin Signaling Pathway in Rat Intestine and Brain. International Journal of Molecular Sciences. 2023; 24(6):5438. https://doi.org/10.3390/ijms24065438
Chicago/Turabian StyleLiu, Huayan, Min Liang, Yulin Deng, and Yujuan Li. 2023. "Simulated Microgravity Alters P-Glycoprotein Efflux Function and Expression via the Wnt/β-Catenin Signaling Pathway in Rat Intestine and Brain" International Journal of Molecular Sciences 24, no. 6: 5438. https://doi.org/10.3390/ijms24065438