RESUMO
Currently, no effective treatment exists for premature ovarian failure (POF). To obtain compounds with protective effects against POF, we aimed to design and synthesize a series of spiroheterocyclic protective agents with a focus on minimizing toxicity while enhancing their protective effect against cisplatin-induced POF. This was achieved through systematic modifications of Michael receptors and linkers within the molecular structure of 1,5-diphenylpenta-1,4-dien-3-one analogs. To assess the cytotoxicity and activity of these compounds, we constructed quantitative conformational relationship models using an artificial intelligence random forest algorithm, resulting in R2 values exceeding 0.87. Among these compounds, j2 exhibited optimal protective activity. It significantly increased the survival of cisplatin-injured ovarian granulosa KGN cells, improved post-injury cell morphology, reduced apoptosis, and enhanced cellular estradiol (E2) levels. Subsequent investigations revealed that j2 may exert its protective effect via a novel mechanism involving the activation of the SIRT1/AKT signal pathway. Furthermore, in cisplatin-injured POF in rats, j2 was effective in increasing body, ovarian, and uterine weights, elevating the number of follicles at all levels in the ovary, improving ovarian and uterine structures, and increasing serum E2 levels in rats with cisplatin-injured POF. In conclusion, this study introduces a promising compound j2 and a novel target SIRT1 with substantial protective activity against cisplatin-induced POF.
RESUMO
Objective: This study aimed to compare the variability of HPV16/18/52/58 subtype infections in patients with different cervical lesions, to explore the guiding significance of persistent positive HPV subtypes 52 and 58 in the stratified management of cervical lesions, and to determine the appropriate management model. Method: This study was conducted through a retrospective analysis of 244,218 patients who underwent HPV testing at the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University from September 2014 to December 2020 to examine the distribution of different types of HPV infection. From March 2015 to September 2017, 3,014 patients with known HPV underwent colposcopy to analyze high-risk HPV infection for different cervical lesions. Meanwhile, from September 2014 to December 2020, 1,616 patients positive for HPV16/18/52/58 alone with normal TCT who underwent colposcopy in our hospital were retrospectively analyzed for the occurrence of cervical and vulvovaginal lesions, with colposcopic biopsy pathology results serving as the gold standard for statistical analysis. Result: Analysis of 244,218 patients who had HPV tested revealed that the top 3 high-risk HPV types were HPV52, HPV58, and HPV16. Further analysis of 3,014 patients showed that 78.04% of patients referred for colposcopy had HPV16/18/52/58 alone. Among high-grade squamous intraepithelial lesions (HSIL) and cervical cancer, the most common is HPV16, followed by HPV58 and then HPV52 (p < 0.05). A total of 1,616 patients with normal TCT who were referred for colposcopy due to HPV16/18/52/58 infection were further analyzed. Based on pathological findings in lesions of HSIL and CC, HPV16 is the most common, followed by HPV58 and then HPV18 (p < 0.05). In the 1,616 patients analyzed, high-grade vulvovaginal lesions were detected, with HPV58 being the most common, followed by HPV16 and then HPV52 (p < 0.05). Conclusion: 1. In patients with positive HPV58 alone and normal TCT, the indications for colposcopy may be relaxed, with particular attention paid to the possibility of vulvar and vaginal lesions.2. Patients with a positive HPV type 52 alone and normal TCT may be considered for a follow-up review and, if necessary, a colposcopy.3. The development of a more suitable HPV vaccine for the Asian population, such as HPV16/18/52/58, may better protect women's health.
RESUMO
Background: Midazolam is a neurological drug with diverse functions, including sedation, hypnosis, decreased anxiety, anterograde amnesia, brain-mediated muscle relaxation, and anticonvulsant activity. Since it is frequently used in children and adolescents for extended periods of time, there is a risk that it may affect their pubertal development. Here, we report a potential effect of the drug on the development of Leydig cells (LCs), the testosterone (T)-producing cells in the testis. Methods: Stem LCs (SLCs), isolated from adult rat testes by a magnetic-activated cell sorting technique, were induced to differentiate into LCs in vitro for 3 weeks. Midazolam (0.1-30 µM) was added to the culture medium, and the effects on LC development were assayed. Results: Midazolam has dose-dependent effects on SLC differentiation. At low concentrations (0.1-5 µM), the drug can mildly increase SLC differentiation (increased T production), while at higher concentrations (15-30 µM), it inhibits LC development (decreased T production). T increases at lower levels may be due to upregulations of scavenger receptor class b Member 1 (SCARB1) and cytochrome P450 17A1 (CYP17A1), while T reductions at higher levels of midazolam could be due to changes in multiple steroidogenic proteins. The uneven changes in steroidogenic pathway proteins, especially reductions in CYP17A1 at high midazolam levels, also result in an accumulation of progesterone. In addition to changes in T, increases in progesterone could have additional impacts on male reproduction. The loss in steroidogenic proteins at high midazolam levels may be mediated in part by the inactivation of protein kinase B/cAMP response element-binding protein (AKT/CREB) signaling pathway. Conclusion: Midazolam has the potential to affect adult Leydig cell (ALC) development at concentrations comparable with the blood serum levels in human patients. Further studies are needed to test the effects on human cells.
