Antioxidative and Energy Metabolism-Improving Effects of Maca Polysaccharide on Cyclophosphamide-Induced Hepatotoxicity Mice via Metabolomic Analysis and Keap1-Nrf2 Pathway
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Reagents
2.3. Animals
2.4. Experimental Design
2.5. Bodyweight and Daily Observation
2.6. Sample Collection
2.7. Histopathological Analysis of Livers
2.8. Assessment of Liver Function Transferases
2.9. Determination of Hepatic Oxidative Stress Markers
2.10. Determination of ATPases in Liver Tissue
2.11. Hepatic Metabolomic Analysis
2.11.1. Liver Sample Metabolite Extraction and QC Sample Preparation
2.11.2. LC-MS/MS Analysis
2.11.3. Data Preprocessing and Multivariate Data Analysis
2.11.4. Metabolite Identification
2.12. Quantitative Real-Time PCR Analysis
2.13. Determination of Protein Expression Level Using Western Blotting
2.14. Statistical Analysis
3. Results
3.1. Effects of Maca Polysaccharide on General Conditions and Body Weights of CYP-Treated Mice
3.2. Maca Polysaccharide Alleviates Liver Histopathological Changes Induced by CYP
3.3. Maca Polysaccharide Reduces the Levels of Serum Transaminase in CYP-Induced Hepatotoxicity Mice
3.4. Maca Polysaccharide Reduces Oxidative Stress
3.5. Effect of Maca Polysaccharide on the Mitochondrial Energy Metabolism in the Liver Tissues of CYP-Treated Mice
3.6. Hepatic Metabolomic Analysis Based on PCA and OPLS-DA
3.7. Screening and Identification for Potential Biomarkers
3.8. Metabolic Pathway of Potential Biomarkers
3.9. Correlation Analysis between Potential Biomarkers and Biochemical Indices
3.10. Maca Polysaccharide Activates Protective Antioxidant Mechanisms via Keap1-Nrf2 Signaling after Cyclophosphamide Chanllenge
4. Discussion
4.1. MP Alleviates Cyclophosphamide-Induced Hepatotoxicity in Mice by Ameliorating Oxidative Stress and Improving Energy Metabolism
4.2. MP Regulates the Potential Metabolic Markers and Pathways Associated with CYP-Induced Hepatotoxicity
4.3. Maca Polysaccharide Attenuates CYP-Induced Hepatotoxicity via Keap1-Nrf2 Antioxidative Pathway
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Acknowledgments
Conflicts of Interest
Abbreviations
SOD | superoxide dismutase |
CAT | catalase |
LDH | lactate dehydrogenase |
LPO | lipid peroxidation |
MP | Maca polysaccharide |
CYP | cyclophosphamide |
ROS | reactive oxygen species |
ALT | alanine aminotransferase |
AST | aspartate transaminase |
MDA | malondialdehyde |
GSH-Px | glutathione peroxidase |
Rha | rhamnose |
Ara | arabinose |
Glc | glucose |
Gal | galactose |
i.p. | intraperitoneal |
NADH | nicotinamide adenine dinucleotide |
QC | quality control |
PCA | principal component analysis |
OPLS-DA | orthogonal projection to latent structure discriminate analysis |
VIP | variable importance in projection |
KEGG | Kyoto Encyclopedia of Genes and Genomes |
RT-qPCR | real-time fluorescence quantitative polymerase chain reaction |
Nrf2 | nuclear factor (erythroid-derived 2)-like 2 |
Keap1 | kelch-like ECH-associated protein 1 |
HO-1 | heme oxygenase 1 |
Gclc | glutamate cysteine ligase catalytic subunit |
Nqo1 | NAD(P) H dehydrogenase quinone 1 |
Cv | central veins |
Vd | vacuolar degeneration |
Fd | fatty degeneration |
PLA2 | phospholipase A2 |
HCY | homocysteine |
PRPP | 5-phosphate-alpha-d-ribose 1-diphosphate |
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Genes | Forward (5′–3′) | Reverse (5′–3′) |
---|---|---|
Nrf2 | CCTTTGGAGGCAAGACATAGATC | CATCTACAAATGGGAATGTCTCTG |
Keap1 | GAGATATGAGCCAGAGCGGGA | AACTGGTCCTGCCCATCGTAG |
HO-1 | AACTTTCAGAAGGGTCAGGTGTC | CTCCTCAGGGAAGTAGAGTGGG |
Gclc | CTGTAGATGATAGAACACGGGAGG | GAGATGAGCAACGTGCTGTGC |
Nqo1 | GCGAGAAGAGCCCTGATTGT | AGATGACTCGGAAGGATACTGAAA |
GAPDH | CCTCGTCCCGTAGACAAAATG | TGAGGTCAATGAAGGGGTCGT |
No. | Differential Metabolites | Mode | CYP vs. NC | MP+CYP vs. CYP | ||||
---|---|---|---|---|---|---|---|---|
VIP | FC | Trend | VIP | FC | Trend | |||
1 | Glycerophosphocholine | ESI+ | 1.66 | 0.80 | ↓ * | 1.08 | 1.08 | ↑ * |
2 | LysoPA(18:1(9Z)/0:0) | ESI− | 1.2 | 0.71 | ↓ * | 1.69 | 1.27 | ↑ * |
3 | 4-Trimethylammoniobutanoic acid | ESI+ | 1.11 | 0.72 | ↓ * | 1.60 | 1.42 | ↑ * |
4 | Uridine | ESI+ | 2.07 | 0.82 | ↓ ** | 1.29 | 1.18 | ↑ * |
5 | Orotidine | ESI− | 2.22 | 0.71 | ↓ *** | 1.37 | 1.37 | ↑ * |
6 | S-Adenosylhomocysteine | ESI+ | 2.05 | 0.75 | ↓ * | 1.06 | 1.30 | ↑ * |
7 | L-Methionine | ESI+ | 1.58 | 0.88 | ↓ * | 1.70 | 1.17 | ↑ * |
8 | Uracil | ESI− | 1.82 | 1.24 | ↓ * | 1.12 | 1.02 | ↑ * |
9 | LysoPC(20:4(8Z,11Z,14Z,17Z)) | ESI+ | 1.95 | 1.67 | ↑ * | 1.71 | 0.64 | ↓ * |
10 | Deoxycytidine | ESI− | 1.84 | 0.76 | ↑ * | 1.20 | 0.76 | ↓ * |
11 | 8,9-DiHETrE | ESI− | 1.59 | 1.63 | ↑ * | 1.16 | 0.70 | ↓ * |
12 | 2-Amino-3,8-dimethyl-3H-imidazo [4,5-f]quinoxaline | ESI+ | 2.45 | 2.24 | ↑ *** | 2.37 | 0.43 | ↓ *** |
13 | Ribose 1-phosphate | ESI− | 1.47 | 1.33 | ↑ * | 1.58 | 0.74 | ↓ * |
14 | PC(16:1(9Z)/16:1(9Z)) | ESI+ | 1.19 | 2.23 | ↑ * | 1.57 | 0.36 | ↓ * |
15 | Tetraacetylethylenediamine | ESI+ | 2.14 | 2.25 | ↑ *** | 2.56 | 0.35 | ↓ *** |
16 | D-4′-Phosphopantothenate | ESI+ | 1.38 | 1.53 | ↑ * | 1.67 | 0.62 | ↓ * |
17 | PC(22:5(4Z,7Z,10Z,13Z,16Z)/20:5(5Z,8Z,11Z,14Z,17Z)) | ESI+ | 1.45 | 1.29 | ↑ * | 1.75 | 0.75 | ↓ * |
18 | Saccharopine | ESI− | 2.55 | 2.16 | ↑ *** | 2.47 | 0.40 | ↓ *** |
19 | N-Acetylglutamic acid | ESI− | 1.77 | 1.27 | ↑ * | 2.33 | 0.68 | ↓ *** |
20 | Sedoheptulose | ESI+ | 1.27 | 1.79 | ↑ * | 1.99 | 0.42 | ↓ ** |
21 | Homocitrulline | ESI+ | 1.71 | 1.36 | ↑ * | 1.77 | 0.66 | ↓ * |
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Fei, W.; Zhang, J.; Yu, S.; Yue, N.; Ye, D.; Zhu, Y.; Tao, R.; Chen, Y.; Chen, Y.; Li, A.; et al. Antioxidative and Energy Metabolism-Improving Effects of Maca Polysaccharide on Cyclophosphamide-Induced Hepatotoxicity Mice via Metabolomic Analysis and Keap1-Nrf2 Pathway. Nutrients 2022, 14, 4264. https://doi.org/10.3390/nu14204264
Fei W, Zhang J, Yu S, Yue N, Ye D, Zhu Y, Tao R, Chen Y, Chen Y, Li A, et al. Antioxidative and Energy Metabolism-Improving Effects of Maca Polysaccharide on Cyclophosphamide-Induced Hepatotoxicity Mice via Metabolomic Analysis and Keap1-Nrf2 Pathway. Nutrients. 2022; 14(20):4264. https://doi.org/10.3390/nu14204264
Chicago/Turabian StyleFei, Wenting, Jianjun Zhang, Shuhui Yu, Na Yue, Danni Ye, Yingli Zhu, Ran Tao, Yan Chen, Yawen Chen, Aimin Li, and et al. 2022. "Antioxidative and Energy Metabolism-Improving Effects of Maca Polysaccharide on Cyclophosphamide-Induced Hepatotoxicity Mice via Metabolomic Analysis and Keap1-Nrf2 Pathway" Nutrients 14, no. 20: 4264. https://doi.org/10.3390/nu14204264