Ovarian cancer is a gynecological tumor with extremely high mortality and poor prognosis. Exosomes derived from tumor cells contain abundant proteins that may influence tumor metastasis. The purpose of our study was to explore the proteomic profile of serum exosomes from epithelial ovarian cancer (EOC) patients and to find potential diagnostic markers for EOC. We obtained purified exosomes from serum using ultracentrifugation. Migration assay was used to evaluate the effects of exosomes on the migration of EOC cells. Proteomic profile of serum exosomes was analyzed by liquid chromatogram-tandem mass spectrometry. The levels of low-density lipoprotein receptor-related protein 1 (LRP1) in serum and serum exosomes were determined by enzyme-linked immunosorbent assay. Western blot and Immunohistochemistry were used to determine the level of LRP1 in tissues. Moreover, we performed small-interfering RNA-mediated knockdown of LRP1 in EOC cells to obtain SI-LRP1-Exos and SI-NC-Exos. The detailed mechanisms by which exosomal LRP1 affected the migration of EOC cells in vitro and in vivo were also explored. We found that serum exosomes from EOC patients contributed to the migration of EOC cells. The level of serum exosomal LRP1 of EOC patients was significantly upregulated compared with that of healthy volunteers, which was consistent with the result of enzyme-linked immunosorbent assay. We found that exosomal LRP1 regulated the expression of MMP2 and MMP9 through ERK signaling pathway and affected the migration of EOC cells in vitro and in vivo. Therefore, we propose that exosomal LRP1 contributes to the migration of EOC and may act as an important diagnostic and prognostic biomarker of EOC.

Background: Gynecological malignancies, such as endometrial cancer (EC) and uterine cancer are prevalent. Increased Acyl-CoA synthetase long-chain family member 1 (ACSL1) activity may contribute to aberrant lipid metabolism, which is a potential factor that contributes to the pathogenesis of endometrial cancer. This study aimed to elucidate the potential molecular mechanisms by which ACSL1 is involved in lipid metabolism in endometrial cancer, providing valuable insights for targeted therapeutic strategies. Methods: Xenograft mouse models were used to assess the effect of ACSL1 on the regulation of endometrial cancer progression. ACSL1 protein levels were assessed via immunohistochemistry and immunoblotting analysis. To assess the migratory potential of Ishikawa cells, wound-healing and Transwell invasion assays were performed. Changes in lipids in serum samples from mice with endometrial cancer xenotransplants were examined in an untargeted lipidomic study that combined multivariate statistical methods with liquid chromatography‒mass spectrometry (LC/MS). Results: Patient sample and tissue microarray data suggested that higher ACSL1 expression is strongly associated with the malignant progression of EC. Overexpression of ACSL1 enhances fatty acid β-oxidation and 5′-adenylate triphosphate (ATP) generation in EC cells, promoting cell proliferation and migration. Lipidomic analysis revealed that significant changes were induced by ACSL1, including changes to 28 subclasses of lipids and a total of 24,332 distinct lipids that were detected in both positive and negative ion modes. Moreover, pathway analysis revealed the predominant association of these lipid modifications with the AMPK/CPT1C/ATP pathway and fatty acid β-oxidation. Conclusions: This study indicates that ACSL1 regulates the AMPK/CPT1C/ATP pathway, which induces fatty acid β-oxidation, promotes proliferation and migration, and then leads to the malignant progression of EC.

Background: Tamoxifen treatment may induce dysregulation of estrogen homeostasis, leading to the occurrence of related adverse reactions. However, the potential mechanisms are still unclear. The purpose of the present study was to uncover whether tamoxifen treatment would act on estrogen metabolism-related biological enzymes and the regulatory effect on estrogen homeostasis to clarify the key factors and potential mechanisms of adverse reactions caused by long-term use of tamoxifen. Method: Female SD rats were administrated with tamoxifen CMC-Na solution (p.o.) once daily for four weeks and then housed at room temperature. Serum, breast, liver, uterus, and ovarian tissues were obtained, and the effects of tamoxifen administration on estrogen homeostasis, the expression, and activity of estrogen metabolic enzyme were evaluated. Results: Compared with the control group, the estrogen homeostasis was disturbed and the expression and activity of UGT2B1 (homology with human UGT2B7) were significantly reduced in the rats administrated with tamoxifen. The inhibitory effect of tamoxifen on UGT2B7 was dominated by hydrophobic and π-π stacking interactions, resulting in a concentration-dependent inhibition of UGT2B7 activity by tamoxifen and the imbalance of ligand-activated transcription factors, leading to abnormal regulation of UGT2B and disturbance of estrogen homeostasis, which in turn led to adverse reactions of tamoxifen. Conclusion: We established links between estrogen metabolism and tamoxifen administration and we proposed that the UGT2B inhibition was involved in the disturbance of estrogen homeostasis and the occurrence of tamoxifen-related adverse reactions.

Background: The leading cause of end-stage renal disease (ESRD) is diabetic nephropathy (DN). Podocyte damage is an early event in the development of DN. Currently, there is no effective treatment strategy that can slow the progression of DN or reverse its onset. The role of mesenchymal stem cells (MSCs) transplantation in diabetes and its complications has been extensively studied, and diabetic nephropathy has been a major focus. Irbesartan exerts reno-protective effects independent of lowering blood pressure, can reduce the incidence of proteinuria in rats, and is widely used clinically. However, it remains undetermined whether the combined utilization of the angiotensin II receptor antagonist irbesartan and MSCs could enhance efficacy in addressing DN. Methods: A commonly used method for modeling type 2 diabetic nephropathy (T2DN) was established using a high-fat diet and a single low-dose injection of STZ (35 mg/kg). The animals were divided into the following 5 groups: (1) the control group (CON), (2) the diabetic nephropathy group (DN), (3) the mesenchymal stem cells treatment group (MSCs), (4) the irbesartan treatment group (Irb), and (5) the combined administration group (MSC + Irb). MSCs (2 × 10⁶ cells/rat) were injected every 10 days through the tail vein for a total of three injections; irbesartan (30 mg/kg/d) was administered by gavage. Additionally, the safety and homing of mesenchymal stem cells were verified using positron emission tomography (PET) imaging. Results: The combination treatment significantly reduced the UACR, kidney index, IGPTT, HOMA-IR, BUN, serum creatine, and related inflammatory factor levels and significantly improved renal function parameters and the expression of proteins related to glomerular podocyte injury in rats. Moreover, MSCs can homing target to damaged kidneys. Conclusions: Compared to the administration of MSCs or irbesartan alone, the combination of MSCs and irbesartan exerted better protective effects on glomerular podocyte injury, providing new ideas for the clinical application of mesenchymal stem cells.