Melatonin Alleviates Lipopolysaccharide-Induced Abnormal Pregnancy through MTNR1B Regulation of m6A
"> Figure 1
<p>The protective effect of melatonin on mouse embryo implantation. (<b>A</b>) Schematic diagram of the animal experimental design. (<b>B</b>) Changes in the body weight, water consumption, and daily feed intake of pregnant mice. <span class="html-italic">n</span> = 36 independent biological replicates. (<b>C</b>) Implantation sites were indicated by injecting Chicago Sky Blue dye. (<b>D</b>) The number of implantation sites in mice. <span class="html-italic">n</span> = 15 independent biological replicates. (<b>E</b>) The weight of uterus in mice. <span class="html-italic">n</span> = 15 independent biological replicates. (<b>F</b>) The blood glucose values in mice. <span class="html-italic">n</span> = 15 independent biological replicates. (<b>G</b>) Blood was analyzed for the number of RBC, HB, PLT, WBC. RBC: red blood cell; HB: hemoglobin concentration; PLT: platelet count; white blood cell. <span class="html-italic">n</span> = 3 independent biological replicates. (<b>H</b>) Serum hormone analysis in mice. <span class="html-italic">n</span> = 3 independent biological replicates. P4: progesterone; E2: Estradiol-17β; CORT: corticosterone; NOR: noradrenaline. Veh: vehicle treatment group; LPS: LPS treatment group; Mel+LPS: melatonin and LPS co-treatment group; Mel: melatonin treatment group; The data are presented as the mean ± SD. Levels of statistical significance for all data were determined by one-way ANOVA and Tukey’s test (* Indicates significant difference between the two groups; * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001).</p> "> Figure 2
<p>Melatonin alleviates LPS-induced inflammation, autophagy, and apoptosis in uterus. (<b>A</b>) Gene Ontology (GO) enrichment analyses of DEGs between Con and Lps. (<b>B</b>) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs between Con and Lps. The top 21 pathways enriched in KEGG. (<b>C</b>) Uterus cytokine analysis by Luminex. <span class="html-italic">n</span> = 4 independent biological replicates. (<b>D</b>) Violin plots show the expression levels inflammation-related genes mRNAs between Con and Lps. (<b>E</b>) Violin plots show the expression levels autophagy-related genes mRNAs between Con and Lps. <span class="html-italic">n</span> = 3 independent biological replicates. (<b>F</b>) Violin plots show the expression levels apoptosis-related genes mRNAs between Con and Lps. <span class="html-italic">n</span> = 3 independent biological replicates. (<b>G</b>) The mRNA levels of the inflammation-related genes in uterus of mice. <span class="html-italic">n</span> = 3 independent biological replicates. (<b>H</b>) The mRNA levels of the autophagy-related genes in uterus of mice. <span class="html-italic">n</span> = 3 independent biological replicates. (<b>I</b>) The mRNA levels of the apoptosis-related genes in uterus of mice. <span class="html-italic">n</span> = 3 independent biological replicates. Veh: vehicle treatment group; LPS: LPS treatment group; Mel+LPS: melatonin and LPS co-treatment group; Mel: melatonin treatment group; The data are presented as the mean ± SD. Levels of statistical significance for all data were determined by one-way ANOVA and Tukey’s test (* Indicates significant difference between the two groups; * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001).</p> "> Figure 3
<p>Melatonin alleviates LPS-induced elevated m6A levels in uterus. (<b>A</b>) Violin plots show the expression levels of m6A regulaters mRNAs between Con and Lps. <span class="html-italic">n</span> = 3 independent biological replicates. (<b>B</b>) Global m6A levels in the uterus. <span class="html-italic">n</span> = 6 independent biological replicates. (<b>C</b>) The mRNA levels of m6A regulaters in the uterus of mice. <span class="html-italic">n</span> = 3 independent biological replicates. (<b>D</b>) Western blot bands of METTL3 and FTO. <span class="html-italic">n</span> = 3 independent biological replicates. (<b>E</b>) Protein–protein interaction (PPI) network of the significant genes. Using the STRING online database. (<b>F</b>) The mRNA levels of <span class="html-italic">Mtnr1b</span> in the uterus of mice. <span class="html-italic">n</span> = 3 independent biological replicates. (<b>G</b>) Immunohistochemical (IHC) staining of METTL3 and FTO in the uterus on D5. <span class="html-italic">n</span> = 3 independent biological replicates. S: stroma; LE: luminal epithelium; GE: glandular epithelium; Myo: myometrium. Veh: vehicle treatment group; LPS: LPS treatment group; Mel+LPS: melatonin and LPS co-treatment group; Mel: Melatonin treatment group; The data are presented as the mean ± SD. Levels of statistical significance for all data were determined by one-way ANOVA and Tukey’s test (* Indicates significant difference between the two groups; * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001).</p> "> Figure 4
<p>m6A-seq analysis of m6A modification after melatonin and LPS stimulation. (<b>A</b>) The annotation of m6A-seq different reads between different treatments. (<b>B</b>) Genome browser view of m6A-seq different reads between different treatments. (<b>C</b>) The motif of m6A-seq different reads between different treatments. (<b>D</b>) Violin plots of the m6A-up and m6A-down genes between different treatments. (<b>E</b>) KEGG pathway enrichment of m6A-up genes between LPS group and Veh group. (<b>F</b>) GO enrichment of m6A-up genes between LPS group and Veh group. (<b>G</b>) Venn diagram of m6A-up genes in the LPS group and m6A-down genes in the Mel+LPS group. (<b>H</b>) Venn diagram of m6A-down genes in the LPS group and m6A-up genes in the Mel+LPS group. <span class="html-italic">n</span> = 3 independent biological replicates. Veh: vehicle treatment group; LPS: LPS treatment group; Mel+LPS: melatonin and LPS co-treatment group.</p> "> Figure 5
<p>Melatonin alleviates LPS-induced inflammation, autophagy, and apoptosis in human endometrial stromal cells. (<b>A</b>) Cell proliferation assay by CCK8 method. <span class="html-italic">n</span> = 6 independent biological replicates. LPS: added LPS only; Mel+LPS: added melatonin and LPS; * Indicates a significant difference compared with the LPS 0 μg/mL group; * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; <sup>#</sup> Indicates a significant difference compared with the LPS 50 μg/mL group; <sup>#</sup> <span class="html-italic">p</span> < 0.05; <sup>##</sup> <span class="html-italic">p</span> < 0.01. (<b>B</b>) Western blot bands of inflammation-related proteins in human endometrial stromal cells. <span class="html-italic">n</span> = 3 independent biological replicates. (<b>C</b>) Western blot bands of autophagy related proteins in human endometrial stromal cells. <span class="html-italic">n</span> = 3 independent biological replicates. (<b>D</b>) Western blot bands of apoptosis related proteins in human endometrial stromal cells. <span class="html-italic">n</span> = 3 independent biological replicates. Veh: vehicle treatment group; LPS: LPS treatment group; Mel+LPS: melatonin and LPS co-treatment group; Mel: melatonin treatment group; The data are presented as the mean ± SD. Levels of statistical significance for all data were determined by one-way ANOVA and Tukey’s test (* Indicates significant difference between the two groups; * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001).</p> "> Figure 6
<p>Melatonin alleviates LPS-induced elevated m6A levels in human endometrial stromal cells. (<b>A</b>) Global m6A levels of human endometrial stromal cells treated with LPS and different concentrations of melatonin. <span class="html-italic">n</span> = 3 independent biological replicates. (<b>B</b>) The mRNA levels of the m6A regulators in uterus of human endometrial stromal cells treated with LPS and melatonin. <span class="html-italic">n</span> = 3 independent biological replicates. (<b>C</b>) Immunofluorescence of m6A-related proteins in HESCs. (<b>D</b>) Immunofluorescence of MTNR1B in HESCs. (<b>E</b>) The ratio of the fluorescence intensity of METTL3 in the nucleus to the fluorescence intensity of METTL3 in the whole cell. <span class="html-italic">n</span> = 6 independent biological replicates. (<b>F</b>) The ratio of the fluorescence intensity of FTO in the nucleus to the fluorescence intensity of FTO in the whole cell. <span class="html-italic">n</span> = 6 independent biological replicates. (<b>G</b>) The ratio of the fluorescence intensity of MTNR1B in the nucleus to the fluorescence intensity of MTNR1B in the whole cell. <span class="html-italic">n</span> = 6 independent biological replicates. (<b>H</b>) The mRNA levels of <span class="html-italic">MTNR1B</span> in the uterus of mice. The experiments were performed in triplicate. The data are presented as the mean ± SD. Levels of statistical significance for all data were determined by one-way ANOVA and Tukey’s test (* Indicates significant difference between the two groups; * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001).</p> "> Figure 7
<p>Melatonin plays a protective role through MTNR1B. (<b>A</b>) Cell proliferation assay by CCK8 method. <span class="html-italic">n</span> = 6 independent biological replicates. 4-P-PDOT: 4-phenyl-2-propionamidotetralin; SAH: S-adenosylhomocysteine; * Indicates a significant difference compared with the 4-P-PDOT/SAH 0 μM group; * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001; <sup>#</sup> Indicates a significant difference compared with the LPS added group alone Difference; <sup>#</sup> <span class="html-italic">p</span> < 0.05; <sup>##</sup> <span class="html-italic">p</span> < 0.01; <sup>###</sup> <span class="html-italic">p</span> < 0.001. (<b>B</b>) Global m6A levels of human endometrial stromal cells treated with 4PPDOT. (<b>C</b>) Western blot bands of inflammation-related proteins in human endometrial stromal cells. (<b>D</b>) Immunoblot analysis of <span class="html-italic">p</span>-RELA, RELA, ERK1/2. (<b>E</b>) Western blot bands of autophagy related proteins in human endometrial stromal cells. (<b>F</b>) Immunoblot analysis of LC3B, ATG5, ATG7. (<b>G</b>) Western blot bands of apoptosis related proteins in human endometrial stromal cells. (<b>H</b>) Immunoblot analysis of c-PARP, BAX, CASP1, c-CASP3. (<b>I</b>) Flow cytometry was used to detect apoptosis after adding the 4PPDOT and melatonin, and apoptosis cells were measured. <span class="html-italic">n</span> = 3 independent biological replicates. Veh: vehicle treatment group; LPS: LPS treatment group; Mel+LPS: melatonin and LPS co-treatment group; Mel: melatonin treatment group; The data are presented as the mean ± SD. Levels of statistical significance for all data were determined by one-way ANOVA and Tukey’s test (* Indicates significant difference between the two groups; * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001).</p> "> Figure 8
<p>The mechanism by which melatonin protects pregnancy.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Melatonin Protects against LPS-Induced Early Pregnancy Abnormalities in Mice
2.2. Melatonin Alleviates LPS-Induced Inflammation, Autophagy and Apoptosis in the Uterus
2.3. Melatonin Alleviates Elevated m6A Levels Induced by LPS in the Uterus
2.4. Melatonin Alleviates LPS-Induced Inflammation, Autophagy, and Apoptosis in HESCs
2.5. Melatonin Alleviates LPS-Induced Elevated m6A Levels in HESCs
2.6. Melatonin Plays a Protective Role through MTNR1B
3. Discussion
4. Materials and Methods
4.1. Animals and Organ Collection
4.2. Cell Culture and Treatment
4.3. Blood Index Detection Method
4.4. Luminex Liquid Suspension Chip Detection
4.5. Quantitative Analysis of m6A Level Using LC-MS/MS
4.6. m6A-Seq
4.7. Identification and Functional Assessment of DEGs
4.8. Protein–Protein Interaction (PPI) Network Construction
4.9. Immunohistochemistry
4.10. Immunofluorescence
4.11. Total RNA Extraction and Quantitative Real-Time PCR (qPCR)
4.12. Western Blot
4.13. CCK-8 Cell Viability Assay
4.14. Flow Cytometry to Detect Cell Apoptosis
4.15. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Zhao, S.; Dong, Y.; Li, Y.; Wang, Z.; Chen, Y.; Dong, Y. Melatonin Alleviates Lipopolysaccharide-Induced Abnormal Pregnancy through MTNR1B Regulation of m6A. Int. J. Mol. Sci. 2024, 25, 733. https://doi.org/10.3390/ijms25020733
Zhao S, Dong Y, Li Y, Wang Z, Chen Y, Dong Y. Melatonin Alleviates Lipopolysaccharide-Induced Abnormal Pregnancy through MTNR1B Regulation of m6A. International Journal of Molecular Sciences. 2024; 25(2):733. https://doi.org/10.3390/ijms25020733
Chicago/Turabian StyleZhao, Shisu, Yanjun Dong, Yuanyuan Li, Zixu Wang, Yaoxing Chen, and Yulan Dong. 2024. "Melatonin Alleviates Lipopolysaccharide-Induced Abnormal Pregnancy through MTNR1B Regulation of m6A" International Journal of Molecular Sciences 25, no. 2: 733. https://doi.org/10.3390/ijms25020733