Nuciferine protects against lipopolysaccharide-induced endometritis via inhibiting ferroptosis and modulating AMPKα/mTOR/HIF-1α signaling axis

by Selleckchem | Nov 16 2023

Nuciferine (NF) is an alkaloid isolated from Nelumbo nucifera and has been reported to exhibit a wide range of pharmacological effects. However, whether NF treatment exhibits a protective effect in endometritis remains unclear. Here, the protective effects of NF on lipopolysaccharide (LPS)-induced endometritis in mice were investigated in our research. The results showed that NF significantly reversed the uterine histopathological changes, inflammatory factor levels and myeloperoxidase (MPO) activity caused by LPS. Furthermore, we found that NF administration improved the reproductive capacity of mice with endometritis. Mechanistically, the expression of MyD88/nuclear factor-kappa B (NF-κB) and MAPK-related proteins in uterine tissue were decreased by NF treatment. Moreover, we observed the occurrence of ferroptosis in the LPS-induced endometritis mouse model, which was noticeably inhibited by NF treatment. In addition, we showed that NF exhibited anti-endometritis activity by modulating AMPKα/mTOR/HIF1α signaling axis. Finally, the molecular mechanism of the NF anti-inflammatory effect was clarified in mouse endometrial epithelial cells (mEECs). NF inhibited the releases of pro-inflammatory factors in LPS-induced mEECs via inhibiting NF-κB signaling pathway. All these findings suggest that NF may ameliorate LPS-induced endometritis caused by LPS, the mechanism of action is related to the ferroptosis, MyD88/NF-κB, MAPK and AMPKα/mTOR/HIF1α signaling pathway.

Comments:

The research you're describing investigates the potential protective effects of Nuciferine (NF), an alkaloid isolated from Nelumbo nucifera, in the context of lipopolysaccharide (LPS)-induced endometritis in mice. Here's a breakdown of the key findings and mechanisms identified in this study:

1. **Uterine Histopathological Changes**: NF treatment significantly reversed the uterine histopathological changes induced by LPS. This suggests that NF has a protective effect on the structure and integrity of the uterine tissue in endometritis.

2. **Inflammatory Factors**: NF treatment reduced the levels of inflammatory factors in the uterine tissue. This indicates that NF can mitigate the inflammatory response associated with endometritis.

3. **Myeloperoxidase (MPO) Activity**: NF also reduced MPO activity. MPO is an enzyme found in neutrophils and is a marker of inflammation. Lower MPO activity suggests reduced inflammation in the uterine tissue.

4. **Reproductive Capacity Improvement**: NF administration improved the reproductive capacity of mice with endometritis. This could imply that NF helps in restoring normal reproductive function that might be compromised due to endometritis.

5. **Mechanistic Insights**:
- **MyD88/NF-κB Pathway**: NF treatment decreased the expression of MyD88 and nuclear factor-kappa B (NF-κB) in uterine tissue. MyD88 is a key adaptor molecule in Toll-like receptor (TLR) signaling, and NF-κB is a transcription factor involved in inflammation. The downregulation of these proteins suggests that NF acts by modulating this pathway, which is critical in the innate immune response.

- **MAPK Pathway**: NF treatment also affected MAPK-related proteins in uterine tissue. The Mitogen-Activated Protein Kinase (MAPK) pathway is another signaling pathway involved in inflammation and cellular responses. NF appears to influence this pathway as well.

- **Ferroptosis**: Ferroptosis is a form of regulated cell death characterized by lipid peroxidation. NF treatment inhibited the occurrence of ferroptosis in the LPS-induced endometritis mouse model. This suggests that NF may protect uterine tissue by preventing ferroptosis, a process that can exacerbate tissue damage.

- **AMPKα/mTOR/HIF1α Signaling Axis**: NF was found to modulate this signaling axis. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are involved in cellular energy regulation and various cellular processes. Hypoxia-inducible factor 1-alpha (HIF1α) is related to oxygen homeostasis and inflammation. NF's effect on this axis may contribute to its protective effects.

6. **Anti-Inflammatory Effect in Mouse Endometrial Epithelial Cells (mEECs)**: In mEECs stimulated with LPS, NF inhibited the release of pro-inflammatory factors. This effect was mediated by the inhibition of the NF-κB signaling pathway. This indicates that NF can directly act on endometrial cells to reduce inflammation.

In summary, the study suggests that Nuciferine (NF) has a potential protective effect against LPS-induced endometritis in mice. Its mechanisms of action involve modulation of the MyD88/NF-κB and MAPK pathways, inhibition of ferroptosis, and regulation of the AMPKα/mTOR/HIF1α signaling axis. Additionally, NF exerts anti-inflammatory effects by inhibiting NF-κB signaling in endometrial epithelial cells. These findings provide insights into the potential therapeutic benefits of NF in the context of endometritis.