The aim of this study was to investigate the functional responses of umbilical arteries and myometrial smooth muscle tissue from pregnant women with intrahepatic cholestasis and healthy pregnant women to the calcium channel blocker nifedipine and the K⁺ channel opener NS11021, and to evaluate histopathological findings. Umbilical arteries and myometrium were isolated immediately after delivery from 8 healthy and 7 cholestatic pregnant women, and smooth muscle responses to nifedipine (10⁻8–10⁻5 M) and NS11021 (10⁻8–10⁻6 M) were examined in isolated organ baths. Histopathological and immunohistochemical investigations were also performed. In the cholestasis group, the maximum response and sensitivity to nifedipine and NS11021 in the myometrium were not altered, whereas in the umbilical artery, sensitivity to nifedipine decreased, and both maximum response and sensitivity to NS11021 decreased. Histological examinations demonstrated increased apoptosis in the umbilical artery and myometrium. These findings suggest that intrahepatic cholestasis of pregnancy may be associated with more pronounced alterations in pharmacological responses to nifedipine and NS11021 in the umbilical artery than in the myometrium, which may contribute to fetal complications. Further controlled studies are needed to clarify the pathophysiology of intrahepatic cholestasis of pregnancy and related fetal outcomes.
During pregnancy, the cervix provides mechanical support for the developing fetus and then dynamically remodels during late gestation to soften and enable parturition. Dysfunction of the cervix can therefore lead to preterm birth, a leading cause of neonatal morbidity and mortality. Progestational agents have been extensively studied for preterm birth prevention, yet data on their direct biomechanical impact on the cervix are limited. Therefore, this study aimed to investigate the biomechanical and compositional effects of systemic and vaginal progesterone administration on cervical tissue integrity in mice during late gestation. Pregnant mice received daily systemic or vaginal progesterone from gestational days 14–17 and were compared to vehicle controls. Cervical tissues were harvested six hours after the final treatment for structural, mechanical, and compositional assessment. Systemic progesterone treatment did not produce changes in cervical structure, mechanical properties, or extracellular matrix composition. In contrast, vaginal progesterone increased cervical tangent modulus at different stages of fatigue life. Vaginal progesterone also reduced cervical cross-sectional area and water content, while increasing collagen concentration relative to wet weight, suggesting that its biomechanical effects may be mediated through modulation of tissue hydration. These findings provide a plausible biomechanical basis for the clinical efficacy of vaginal progesterone in preventing preterm birth by preserving cervical mechanical stability and attenuating premature softening.
Ovarian cancer (OC), a leading cause of gynecological cancer mortality, demands deeper molecular understanding. This study investigates the role of Cysteine-Rich Protein 1 (CRIP1) in OC pathogenesis. In this study, CRIP1 expression and its correlation with prognosis were analyzed using public databases and clinical OC tissue samples. OC cell line HEY and SKOV3 were employed in the in vitro experiments. Gene and protein expression were measured by qRT-PCR, Western blotting (WB), immunohistochemistry (IHC), and immunofluorescence (IF). Cell proliferation was assessed via CCK-8 and EDU assays. Cell migration and invasion were evaluated using Transwell and wound healing assays. Protein-protein interaction between CRIP1, KRAS, and USP7 was confirmed by co-immunoprecipitation (Co-IP). The in vivo role of CRIP1 was validated using xenograft mouse models. Our results showed that CRIP1 expression was significantly upregulated in OC tissues compared to adjacent normal tissues, and high CRIP1 expression correlated with poor patient prognosis. Overexpression of CRIP1 enhanced OC cell proliferation, migration, and invasion, while CRIP1 knockdown suppressed these malignant phenotypes. Mechanistically, CRIP1 facilitated the interaction between KRAS and the deubiquitinase USP7, leading to KRAS protein stabilization. CRIP1 overexpression increased USP7-bound KRAS and elevated total KRAS protein levels. Treatment with USP7 inhibitor (P5091) destabilized KRAS. More importantly, KRAS knockdown reversed the effect of CRIP1 overexpression on cell proliferation, migration and invasion. Finally, CRIP1 overexpression significantly accelerated OC progression in xenograft models. Collectively, our findings demonstrate that CRIP1 promotes ovarian cancer progression by mediating the KRAS-USP7 interaction and stabilizing KRAS. This study elucidates a novel molecular mechanism underlying OC progression and identifies CRIP1 as a potential therapeutic target.
The incidence of Uterine Corpus Endometrial Carcinoma (UCEC) is increasing, and the 5-year survival rate for patients with advanced-stage or high-grade disease remains low, underscoring the urgent need for reliable molecular prognostic biomarkers. Metabolic reprogramming is a hallmark of cancer, yet the prognostic role of Vitamin Metabolism-Related Genes (VMRGs) in UCEC remains unclear. Transcriptomic and clinical data for UCEC were retrieved from the TCGA database, while scRNA-seq datasets were procured from the GEO database. WGCNA was used to identify VMRG activity-related co-expression modules. The scRNA-seq dataset was utilized for cell type annotation, malignant cell identification via inferCNV, and cell-cell communication analysis via CellChat. Genes from WGCNA modules and DEGs from malignant cells were intersected to establish a prognostic model with LASSO-Cox regression. Differences in the immune microenvironment, genomic mutations, and drug sensitivity between high- and low-risk groups were further analyzed. qRT-PCR was used to detect the expression of the model genes; a DKC1-knockdown UCEC cell model was constructed, and the effects of DKC1 on cell functions were verified by qRT-PCR, Western blot, CCK-8, colony formation, Transwell, and ELISA assays. WGCNA linked MEgreen and MElightcyan modules to VMRG activity. Malignant epithelial cells showed higher VMRG activity, with IL6 signaling as a key TME-modulating axis. An 8-gene LASSO-Cox model (MT-CO1, MTHFD2, MRPS22, DKC1, TFG, TINF2, CHCHD7, HEBP1) stratified high-risk patients with increased MDSC infiltration and TP53 mutations. High-risk group was sensitive to BI-2536, ML210, obatoclax; low-risk to cediranib, tanespimycin, VAF-347. Cell-based experiments showed that the model genes were differentially expressed; moreover, DKC1 enhanced the sensitivity to BI-2536 and promoted UCEC malignant progression by activating the IL-6/JAK2/STAT3 signaling pathway. The 8-gene prognostic signature developed in this study, associated with VMRG activity, effectively stratifies the risk for UCEC patients, providing a novel reference for prognostic assessment and individualized treatment.
Adenomyosis (ADS) is a common gynecological disorder characterized by dysmenorrhea, menorrhagia, and infertility, which markedly impair women’s quality of life. Repeated cyclic bleeding of ectopic endometrial lesions may sustain local inflammation and tissue remodeling, leading to a “menstruation—inflammation—fibrosis” cycle. This study aimed to establish a mouse model that mimics this process and to evaluate the effect of estrogen-progesterone (EP) sequential exposure on uterine fibrosis in adenomyosis. Methods: A tamoxifen-induced mouse model of adenomyosis was established, followed by EP sequential exposure to induce a menstruation-like process. Histological staining and immunohistochemistry were performed to evaluate lesion formation, inflammatory responses, and fibrosis-related changes in uterine tissues. Results: EP sequential exposure successfully induced menstruation-like changes in the uterus of mice with adenomyosis. Compared with controls, mice exposed to sequential EP showed more prominent endometrial breakdown, inflammatory responses, and fibrotic remodeling. Collagen deposition and the expression of fibrosis-associated markers, including α-SMA, were increased in uterine lesions, indicating aggravated fibrosis. Conclusion: EP sequential exposure promotes fibrosis in adenomyosis lesions in mice and may serve as a useful model for investigating the “menstruation—inflammation—fibrosis” cycle in adenomyosis.
