NEK6 dampens FOXO3 nuclear translocation to stabilize C-MYC and promotes subsequent de novo purine synthesis to support ovarian cancer chemoresistance.

De novo purine synthesis metabolism plays a crucial role in tumor cell survival and malignant progression. However, the specific impact of this metabolic pathway on chemoresistance in ovarian cancer remains unclear. This study aims to elucidate the influence of de novo purine synthesis on chemoresistance in ovarian cancer and its underlying regulatory mechanisms. We analyzed metabolic differences between chemosensitive and chemoresistant ovarian cancer tissues using mass spectrometry-based metabolomics. Cell growth, metabolism, chemoresistance, and DNA damage repair characteristics were assessed in vitro using cell line models. Tumor growth and chemoresistance were assessed in vivo using ovarian cancer xenograft tumors. Intervention of purines and NEK6-mediated purine metabolism on chemoresistance was investigated at multiple levels. Chemoresistant ovarian cancers exhibited higher purine abundance and NEK6 expression. Inhibiting NEK6 led to decreased de novo purine synthesis, resulting in diminished chemoresistance in ovarian cancer cells. Mechanistically, NEK6 directly interacted with FOXO3, contributing to the phosphorylation of FOXO3 at S7 through its kinase activity, thereby inhibiting its nuclear translocation. Nuclear FOXO3 promoted FBXW7 transcription, leading to c-MYC ubiquitination and suppression of de novo purine synthesis. Paeonol, by inhibiting NEK6, suppressed de novo purine synthesis and enhanced chemosensitivity. The NEK6-mediated reprogramming of de novo purine synthesis emerges as a critical pathway influencing chemoresistance in ovarian cancer. Paeonol exhibits the potential to interfere with NEK6, thereby inhibiting chemoresistance.

Increased extracellular matrix stiffness regulates myofibroblast transformation through induction of autophagy-mediated Kindlin-2 cytoplasmic translocation.

The extracellular matrix (ECM) mechanical properties regulate biological processes, such as fibroblast-myofibroblast transformation (FMT), which is a crucial component in pelvic organ prolapse (POP) development. The 'Kindlin-2' protein, expressed by fibroblasts, plays an important role in the development of the mesoderm, which is responsible for connective tissue formation; however, the role of Kindlin-2 in FMT remains to be explored. In this study, we aimed to explore the role of Kindlin-2 in FMT as it relates to POP. We found that ECM stiffness induces autophagy to translocate Kindlin-2 to the cytoplasm of L929 cells, where it interacts with and degrades MOB1, thereby facilitating Yes-associated protein (YAP) entry into the nucleus and influencing FMT progression. Stiffness-induced autophagy was inhibited when using an autophagy inhibitor, which blocked the translocation of Kindlin-2 to the cytoplasm and partially reversed high-stiffness-induced FMT. In patients with POP, we observed an increase in cytoplasmic Kindlin-2 and nuclear YAP levels. Similar changes in vaginal wall-associated proteins were observed in a mouse model of acute vaginal injury. In conclusion, Kindlin-2 is a key gene affecting ECM stiffness, which regulates FMT by inducing autophagy and may influence the development of POP.

Spatiotemporal Trends and Age-Period-Cohort Analysis for the Burden of Endometriosis-Related Infertility: An Analysis of the Global Burden of Disease Study 2019.

BACKGROUND: Endometriosis is a common nonfatal gynecological disease, and infertility is one of its main dangers. Endometriosis-related infertility causes serious damage to women's health and places a burden on women of reproductive age. The aim of this study was to describe the current burden of endometriosis-associated infertility and to analyze its spatiotemporal trends. METHODS: Age-standardized prevalence rate (ASPR) data from 1990 to 2019 for Endometriosis-related primary infertility (ERPI) and secondary infertility (ERSI) were obtained from the Global Burden of Disease Study (GBD) 2019. These data spanning three decades cover the global, sociodemographic index (SDI) regions, GBD regions, and 204 countries and territories. Spatiotemporal trends were analyzed by calculating the estimated annual percentage change (EAPC) and using a time-period-cohort model. RESULTS: Globally, the ASPR of ERPI and ERSI showed a weak downward trend from 1990 to 2019, with EAPCs of -1.25 (95% CI: -1.39 to -1.11) and -0.6 (95% CI: -0.67 to -0.53), respectively. The spatiotemporal trends in ERPI and ERSI varied substantially between regions and age groups. When endometriosis-related infertility burden was linked to SDI values, a strong negative correlation was observed between the ASPR of ERSI and its EAPC and SDI values. When modeling with age-period-cohort, ERPI burden was found to be highest at ages 20-25 years, while ERSI burden was persistently higher at ages 20-45 years. Using 2000-2004 as the reference period, both ERPI and ERSI burden decreased with each year among women. Significant variability in burden between regions was found for the birth cohort factor. CONCLUSIONS: The global burden of endometriosis-related infertility declined minimally from 1990 to 2019. However, this burden varied considerably across regions, age groups, periods, and birth cohorts. The results of this study reflect spatiotemporal trends in the burden of endometriosis-related infertility over the study period and may be used to help improve health management, develop timely and effective prevention and control strategies, and provide epidemiologic theoretical evidence for reducing the burden for endometriosis-related infertility.

Estrogen inhibits the differentiation of fibroblasts induced by high stiffness matrix by enhancing DNMT1 expression.

INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse(POP) is a multifactorial connective tissue disorder caused by damage to the supporting structures of the pelvic floor. Evidence from several studies suggests that anterior vaginal wall stiffness is higher in patients with POP, but the mechanisms involved remain unknown. METHODS: Tissue from the anterior vaginal wall of patients with POP or other benign diseases was obtained. The modulus of elasticity of the anterior vaginal wall was measured using a microindenter. Cells were cultured in vitro on acrylamide gels of different stiffness and treated with DNMT1 inhibitor, microtubule polymerisation inhibitor and estrogen. Western blot or immunohistochemical staining was performed to detect DNA Methyltransferase 1, α-smooth muscle actin(α-SMA) expression, and connective tissue growth factor(CTGF) expression. CONCLUSION: Estrogen can inhibit high stiffness matrix-induced fibroblast differentiation, by enhancing DNMT1 expression. This study may help to elucidate the complex crosstalk between fibroblasts and their surrounding matrix under healthy and pathological conditions and provide new insights into the options for material-related therapeutic applications.

The Global, Regional, and National Uterine Cancer Burden Attributable to High BMI from 1990 to 2019: A Systematic Analysis of the Global Burden of Disease Study 2019.

Uterine cancer (UC) is the most common gynecologic malignancy, and high body mass index (BMI) is a poor prognostic factor for UC. However, the associated burden has not been fully assessed, which is crucial for women's health management and the prevention and control of UC. Therefore, we utilized the Global Burden of Disease Study (GBD) 2019 to describe the global, regional, and national UC burden due to high BMI from 1990 to 2019. The data show that globally, women's high BMI exposure is increasing annually, with most regions having higher rates of high BMI exposure than the global average. In 2019, 36,486 [95% uncertainty interval (UI): 25,131 to 49,165] UC deaths were attributed to high BMI globally, accounting for 39.81% (95% UI: 27.64 to 52.67) of all UC deaths. The age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life years (DALY) rate (ASDR) for high BMI-associated UC remained stable globally from 1990 to 2019, with significant differences across regions. Higher ASDR and ASMR were found in higher socio-demographic index (SDI) regions, and lower SDI regions had the fastest estimated annual percentage changes (EAPCs) for both rates. Among all age groups, the fatal outcome of UC with high BMI occurs most frequently in women over 80 years old.