Glutaminolysis regulates endometrial fibrosis in intrauterine adhesion via modulating mitochondrial function.

BACKGROUND: Endometrial fibrosis, a significant characteristic of intrauterine adhesion (IUA), is caused by the excessive differentiation and activation of endometrial stromal cells (ESCs). Glutaminolysis is the metabolic process of glutamine (Gln), which has been implicated in multiple types of organ fibrosis. So far, little is known about whether glutaminolysis plays a role in endometrial fibrosis. METHODS: The activation model of ESCs was constructed by TGF-ß1, followed by RNA-sequencing analysis. Changes in glutaminase1 (GLS1) expression at RNA and protein levels in activated ESCs were verified experimentally. Human IUA samples were collected to verify GLS1 expression in endometrial fibrosis. GLS1 inhibitor and glutamine deprivation were applied to ESCs models to investigate the biological functions and mechanisms of glutaminolysis in ESCs activation. The IUA mice model was established to explore the effect of glutaminolysis inhibition on endometrial fibrosis. RESULTS: We found that GLS1 expression was significantly increased in activated ESCs models and fibrotic endometrium. Glutaminolysis inhibition by GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES or glutamine deprivation treatment suppressed the expression of two fibrotic markers, α-SMA and collagen I, as well as the mitochondrial function and mTORC1 signaling in ESCs. Furthermore, inhibition of the mTORC1 signaling pathway by rapamycin suppressed ESCs activation. In IUA mice models, BPTES treatment significantly ameliorated endometrial fibrosis and improved pregnancy outcomes. CONCLUSION: Glutaminolysis and glutaminolysis-associated mTOR signaling play a role in the activation of ESCs and the pathogenesis of endometrial fibrosis through regulating mitochondrial function. Glutaminolysis inhibition suppresses the activation of ESCs, which might be a novel therapeutic strategy for IUA.

Abnormal expression of fission and fusion genes and the morphology of mitochondria in eutopic and ectopic endometrium.

Mitochondria play a pivotal role in physiological and metabolic function of the cell. Mitochondrial dynamics orchestrate mitochondrial function and morphology, involving fission and fusion as well as ultrastructural remodeling. Mounting evidence unravels the close link between mitochondria and endometriosis. However, how mitochondrial architecture changes through fission and fusion in eutopic and ectopic tissues of women with ovarian endometriosis remains unknown. We detected the expression of fission and fusion genes and the morphology of mitochondria in eutopic and ectopic endometrium in ovarian endometriosis. The results showed that the expression of DRP1 and LCLAT1 was upregulated in eutopic endometrial stromal cells (ESCs), and the expression of DRP1, OPA1, MFN1, MFN2, and LCLAT1 was significantly downregulated in ectopic ESCs, and reduced number of mitochondria, wider cristae width and narrower cristae junction width was observed, but there was no difference in cell survival rate. The altered mitochondrial dynamics and morphology might, respectively, provide an advantage for migration and adhesion in eutopic ESCs and be the adaptive response in ectopic endometrial cells to survive under hypoxic and oxidative stress environment.

Comparison of Secondary Prevention Following Hysteroscopic Adhesiolysis in the Improvement of Reproductive Outcomes: A Retrospective Cohort Study.

Intrauterine adhesion (IUA) is primarily caused by endometrial injury, and hysteroscopic adhesiolysis is presently the main treatment. However, postoperative recurrence and poor pregnancy outcomes remain intractable. In this study, we aim to assess the effects of different treatments on clinical symptoms and reproductive outcomes in IUA. This retrospective study was conducted in a tertiary university-affiliated women's hospital. The study included 1449 consecutive women who desired to have a baby and were diagnosed with IUA through hysteroscopy from January 2016 to December 2021. Patients with IUA underwent hysteroscopic electric resection (E) or cold scissors separation (C), as well as hormone therapy and one or both of the following secondary prevention measures: intrauterine devices (IUD) and hyaluronic acid gel (HA). The pregnancy rate (PR) was significantly higher in the E + IUD + HA (90.23% CI: 85.82, 94.64%) than in other groups (p = 0.000) groups. The rates of full-term birth (p = 0.000) and live birth (p = 0.000) were significantly higher in the E + IUD + HA (67.82% and 68.97%, respectively) and E + HA (62.41% and 63.91%, respectively) groups. Multivariate logistic regression analysis revealed a significantly higher PR in women who received second-look hysteroscopy (OR 1.571, 95% CI: 1.009-2.224, p = 0.013) and E + IUD + HA (OR 4.772, 95% CI: 2.534-8.987, p = 0.000). Combining hysteroscopic electric resection with IUDs and HA gel could prevent adhesion recurrence and improve postoperative pregnancy and live birth outcomes in IUA. Furthermore, postoperative second-look hysteroscopy may increase the PR and shorten the waiting period.

A nitrogen-doped polyaniline carbon with high electrocatalytic activity and stability for the oxygen reduction reaction in fuel cells.

PANI-BASED CARBON CAT: A low-cost nitrogen-doped carbon nanomaterial from polyaniline as fuel cell cathode electrocatalyst is prepared by chemical polymerization of aniline monomers, followed by pyrolysis in the presence of ammonia. The catalyst demonstrates high activity, with an onset potential comparable to, and a reduction current higher than, a commercial platinum catalyst.