Novel MAGL Inhibitors Alleviate LPS-Induced Acute Kidney Injury by Inhibiting NLRP3 Inflammatory Vesicles, Modulating Intestinal Flora, Repairing the Intestinal Barrier, and Interfering with Serum Metabolism
Abstract
:1. Introduction
2. Results
2.1. The Compound M-18C Functions as an Inhibitor of the Enzyme MAGL
2.2. M-18C Reduces the Levels of TNF-α and IL-1β in the Serum of Mice Caused by LPS
2.3. M-18C Alleviates LPS-Induced AKI in Mice by Inhibiting NLRP3-Mediated Inflammation
2.4. The Administration of M-18C Significantly Reduced NO, TNF-α, and IL-1β Levels and Downregulated NLRP3 and ASC Expression in LPS-induced RAW264.7
2.5. M-18C Protects the Intestinal Barrier Caused by LPS
2.6. M-18C Regulates Imbalance of Gut Microbiota Caused by LPS
2.7. M-18C Regulates Serum Metabolism Caused by LPS
3. Discussion
4. Materials and Methods
4.1. Drugs and Reagents
4.2. Establishment of a Mouse Model of LPS-Induced AKI
4.3. IC50 Determination of MAGL Inhibitor
4.4. Molecular Docking
4.5. Cell Lines and Cell Culture
4.6. Cell Viability Assessment
4.7. Determination of NO
4.8. Western Blotting Assay
4.9. Enzyme-Linked Immunosorbent Assay (ELISA)
4.10. Blood Biochemistry
4.11. Hematoxylin and Eosin (HE) Staining
4.12. Immunohistochemistry (IHC)
4.13. Examining the Influence of M-18C on Serum Metabolism Caused by LPS via Unbiased LC-MS Analysis
4.14. 16S rRNA Gene Sequencing
4.15. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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No. | Name | Formula | RT (min) | Ion Mod | VIP | Model vs. Normal | 2.5 mg/kg vs. Model |
---|---|---|---|---|---|---|---|
1 | 11H-Benzo[a]fluoren-11-ylacetic acid | C19H14O2 | 4.714 | ESI− | 1.23099 | ↓## | ↑* |
2 | 2,4,5,6-Phenanthrenetetrol | C14H10O4 | 8.463 | ESI− | 1.50203 | ↓#### | ↑* |
3 | 2-Dehydro-D-gluconate | C6H10O7 | 1.202 | ESI− | 1.33805 | ↑### | ↓* |
4 | 2-Hydroxy-3-(4-hydroxyphenyl-propenoate | C9H8O4 | 1.882 | ESI− | 1.59186 | ↑## | ↓** |
5 | 2-Methylguanosine | C11H15N5O5 | 4.949 | ESI− | 1.57437 | ↑## | ↓** |
6 | 3,4,5-trimethoxyhydrocinnamic acid | C12H16O5 | 10.617 | ESI− | 1.45642 | ↓#### | ↑* |
7 | 3,4-Dihydroxyphenylglycol O-sulfate | C8H10O7S | 1.612 | ESI− | 1.42525 | ↑## | ↓* |
8 | 3-Bromo-DL-tyrosine | C9H10BrNO3 | 5.655 | ESI− | 1.02757 | ↓# | ↑* |
9 | 3-Oxooctanoic acid | C8H14O3 | 5.061 | ESI− | 1.02523 | ↑## | ↓* |
10 | 4-(4-Deoxy-alpha-D-gluc-4-enuronosyl)-D-galacturonate | C12H16O12 | 1.167 | ESI− | 1.40788 | ↑## | ↓* |
11 | 4-Hydroxybenzaldehyde | C7H6O2 | 4.433 | ESI− | 1.01709 | ↓# | ↑* |
12 | 4-Trifluoromethylphenol | C7H5F3O | 3.941 | ESI− | 1.45253 | ↓#### | ↑* |
13 | 5-Hydroxy-DL-tryptophan | C11H12N2O3 | 3.802 | ESI− | 1.46735 | ↑#### | ↓* |
14 | 5-Hydroxyindole-3-acetic acid | C10H9NO3 | 4.407 | ESI− | 1.47610 | ↑#### | ↓* |
15 | 6-(alpha-D-Glucosaminyl)-1D-myo-inositol | C12H23NO10 | 1.378 | ESI− | 1.47230 | ↑# | ↓** |
16 | 7-Methylxanthine | C6H6N4O2 | 1.854 | ESI− | 1.31582 | ↑# | ↓* |
17 | 8-Amino-7-oxononanoate | C9H17NO3 | 6.475 | ESI− | 1.17585 | ↑## | ↓* |
18 | Adefovir | C8H12N5O4P | 6.24 | ESI− | 1.52359 | ↑#### | ↓* |
19 | Adenine | C5H5N5 | 6.998 | ESI− | 1.05053 | ↓# | ↑* |
20 | Bisphenol S | C12H10O4S | 1.316 | ESI− | 1.44627 | ↑## | ↓* |
21 | Bromazine | C17H20BrNO | 5.243 | ESI− | 1.31946 | ↑# | ↓* |
22 | Butylparaben | C11H14O3 | 10.001 | ESI− | 1.62456 | ↓## | ↑** |
23 | Cascarillin | C22H32O7 | 8.64 | ESI− | 1.27469 | ↑# | ↓* |
24 | cis,cis-Muconic acid | C6H6O4 | 6.379 | ESI− | 1.35960 | ↓## | ↑* |
25 | cis-5-Tetradecenoylcarnitine | C21H39NO4 | 12.571 | ESI− | 1.67272 | ↑### | ↓*** |
26 | Citalopram aldehyde | C18H14FNO2 | 7.431 | ESI− | 1.13161 | ↑## | ↓* |
27 | Coniferin | C16H22O8 | 7.579 | ESI− | 1.26308 | ↑### | ↓* |
28 | Corticosterone | C21H30O4 | 11.773 | ESI− | 1.50496 | ↓#### | ↑** |
29 | Costunolide | C15H20O2 | 11.187 | ESI− | 1.31224 | ↓## | ↑* |
30 | Creatine | C4H9N3O2 | 1.427 | ESI− | 1.70032 | ↑#### | ↓**** |
31 | Diacetyl trimer | C12H18O6 | 1.653 | ESI− | 1.28257 | ↑## | ↓* |
32 | Diflunisal | C13H8F2O3 | 1.809 | ESI− | 1.27618 | ↑## | ↓* |
33 | Doxapram | C24H30N2O2 | 7.239 | ESI− | 1.31590 | ↑## | ↓* |
34 | Forskolin | C22H34O7 | 8.29 | ESI− | 1.34054 | ↑### | ↓* |
35 | Geosmin | C12H22O | 11.826 | ESI− | 1.27614 | ↓## | ↑* |
36 | Gingerenone C | C20H22O4 | 10.646 | ESI− | 1.35761 | ↓### | ↑* |
37 | Gluconic acid | C6H12O7 | 1.219 | ESI− | 1.41214 | ↑### | ↓* |
38 | Guanidinosuccinic acid | C5H9N3O4 | 1.200 | ESI− | 1.31446 | ↑## | ↓* |
39 | Hydrocinnamic acid | C9H10O2 | 7.034 | ESI− | 1.15891 | ↓## | ↑* |
40 | Hydroxycitric acid | C6H8O8 | 1.169 | ESI− | 1.41456 | ↑### | ↓** |
41 | Indole-3-lactic acid | C11H11NO3 | 4.963 | ESI− | 1.45166 | ↓### | ↑** |
42 | Indoxyl-beta-D-glucuronide | C14H15NO7 | 3.785 | ESI− | 1.15719 | ↑## | ↓* |
43 | Jasmonic acid | C12H18O3 | 10.665 | ESI− | 1.44216 | ↓### | ↑* |
44 | L-Histidine | C6H9N3O2 | 1.448 | ESI− | 1.59545 | ↑#### | ↓** |
45 | N4-Acetylcytidine | C11H15N3O6 | 5.189 | ESI− | 1.42193 | ↑### | ↓* |
46 | Nafcillin | C21H22N2O5S | 10.423 | ESI− | 1.14129 | ↓# | ↑* |
47 | Niflumic acid | C13H9F3N2O2 | 1.507 | ESI− | 1.49980 | ↑#### | ↓* |
48 | Quazepam | C17H11ClF4N2S | 1.892 | ESI− | 1.26974 | ↓### | ↑* |
49 | Salicylic acid | C7H6O3 | 5.038 | ESI− | 1.32580 | ↓### | ↑* |
50 | Taurine | C2H7NO3S | 1.318 | ESI− | 1.46605 | ↑#### | ↓* |
51 | Thiolutin | C8H8N2O2S2 | 1.502 | ESI− | 1.27014 | ↑# | ↓* |
52 | Tyrosol | C8H10O2 | 8.738 | ESI− | 1.51769 | ↓## | ↑** |
53 | Uridine | C9H12N2O6 | 3.061 | ESI− | 1.01969 | ↓# | ↑** |
54 | Ascorbic acid | C6H8O6 | 0.910 | ESI+ | 3.63786 | ↑## | ↓* |
55 | Benzamide | C7H7NO | 3.990 | ESI+ | 1.23133 | ↓#### | ↑*** |
56 | Benzoic acid | C7H6O2 | 4.250 | ESI+ | 9.38332 | ↓#### | ↑*** |
57 | Creatine | C4H9N3O2 | 0.916 | ESI+ | 9.34523 | ↑#### | ↓* |
58 | Gluconic acid | C6H12O7 | 0.772 | ESI+ | 2.19480 | ↑### | ↓* |
59 | L-Alanine | C3H7NO2 | 0.917 | ESI+ | 1.63292 | ↑#### | ↓* |
60 | Piperidine | C5H11N | 10.42 | ESI+ | 2.02758 | ↓## | ↑* |
61 | Taurine | C2H7NO3S | 0.812 | ESI+ | 4.30360 | ↑#### | ↓* |
62 | Thiolutin | C8H8N2O2S2 | 0.948 | ESI+ | 1.07162 | ↑#### | ↓** |
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Xiang, H.; Wang, Y.; Yang, L.; Liu, M.; Sun, C.; Gu, Y.; Yao, J. Novel MAGL Inhibitors Alleviate LPS-Induced Acute Kidney Injury by Inhibiting NLRP3 Inflammatory Vesicles, Modulating Intestinal Flora, Repairing the Intestinal Barrier, and Interfering with Serum Metabolism. Molecules 2023, 28, 7245. https://doi.org/10.3390/molecules28217245
Xiang H, Wang Y, Yang L, Liu M, Sun C, Gu Y, Yao J. Novel MAGL Inhibitors Alleviate LPS-Induced Acute Kidney Injury by Inhibiting NLRP3 Inflammatory Vesicles, Modulating Intestinal Flora, Repairing the Intestinal Barrier, and Interfering with Serum Metabolism. Molecules. 2023; 28(21):7245. https://doi.org/10.3390/molecules28217245
Chicago/Turabian StyleXiang, Haixin, Yangui Wang, Lan Yang, Mingfei Liu, Chenghong Sun, Yuchao Gu, and Jingchun Yao. 2023. "Novel MAGL Inhibitors Alleviate LPS-Induced Acute Kidney Injury by Inhibiting NLRP3 Inflammatory Vesicles, Modulating Intestinal Flora, Repairing the Intestinal Barrier, and Interfering with Serum Metabolism" Molecules 28, no. 21: 7245. https://doi.org/10.3390/molecules28217245
APA StyleXiang, H., Wang, Y., Yang, L., Liu, M., Sun, C., Gu, Y., & Yao, J. (2023). Novel MAGL Inhibitors Alleviate LPS-Induced Acute Kidney Injury by Inhibiting NLRP3 Inflammatory Vesicles, Modulating Intestinal Flora, Repairing the Intestinal Barrier, and Interfering with Serum Metabolism. Molecules, 28(21), 7245. https://doi.org/10.3390/molecules28217245