A novel SIK2 inhibitor SIC-19 exhibits synthetic lethality with PARP inhibitors in ovarian cancer.

PURPOSE: Ovarian cancer patients with HR proficiency (HRP) have had limited benefits from PARP inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer. METHODS: The SIK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, AKT-pS473 and MYLK-pS343. SIC-19 emerged as the most promising drug candidate and was further evaluated using multiple assays. RESULTS: SIC-19 exhibited selective and potent inhibition of SIK2, leading to its degradation through the ubiquitination pathway. The IC50 of SIC-19 correlated inversely with endogenous SIK2 expression in ovarian cancer cell lines. Treatment with SIC-19 significantly inhibited cancer cell growth and sensitized cells to PARP inhibitors in vitro, as well as in ovarian cancer organoids and xenograft models. Mechanistically, SIK2 knockdown and SIC-19 treatment reduced RAD50 phosphorylation at Ser635, prevented nuclear translocation of RAD50, disrupted nuclear filament assembly, and impaired DNA homologous recombination repair, ultimately inducing apoptosis. These findings highlight the crucial role of SIK2 in the DNA HR repair pathway and demonstrate the significant PARP inhibitor sensitization achieved by SIC-19 in ovarian cancer. CONCLUSIONS: SIC-19, a novel SIK2 inhibitor, effectively inhibits tumor cell growth in ovarian cancer by interfering with RAD50-mediated DNA HR repair. Furthermore, SIC-19 enhances the efficacy of PARP inhibitors, providing a promising therapeutic strategy to improve outcomes for ovarian cancer patients.

MATN2 overexpression suppresses tumor growth in ovarian cancer via PTEN/PI3K/AKT pathway.

The incidence rate of developing ovarian cancer decreases over the years; however, mortality ranks top among malignancies of women, mainly metastasis through local invasion. Matrilin-2 (MATN2) is a member of the matrilin family that plays an important role in many cancers. However, its relationship with ovarian cancer remains unknown. Our study aimed to explore the function and possible mechanism of MATN2 in ovarian cancer. Human ovarian cancer tissue microarrays were used to detect the MATN2 expression in different types of ovarian cancer using immunohistochemistry (IHC). CCK-8, wound scratch healing assay, transwell assay, and flow cytometry were used to detect cell mobility. Gene and protein expression were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. MATN2 interacts with phosphatase, and the tensin homolog (PTEN) deleted on chromosome 10 was analyzed using TCGA database and co-immunoprecipitation (Co-IP). In vivo experiments were conducted using BALB/c nude mice, and tumor volume and weight were recorded. Tumor growth was determined using hematoxylin and eosin (H&E) and IHC staining. MATN2 was significantly downregulated in ovarian cancer cells. The SKOV3 and A2780 cell mobility was significantly inhibited by MATN2 overexpression, while the cell apoptosis rate was significantly increased. MATN2 overexpression decreased transplanted tumor size in vivo. These results were reversed by inhibiting MATN2. Furthermore, we found that PTEN closely interacted with MATN2 using bioinformatics and Co-IP. MATN2 overexpression significantly inhibited the PI3K/AKT pathway, however, PTEN suppression reversed this effect of MATN2 overexpression. These results indicated that MATN2 may play a critical role in ovarian cancer development by inhibiting cells proliferation and migration. The mechanism was related to interacting with PTEN, thus inhibiting downstream effectors in the PI3K/AKT pathway, which may be a novel target for treating ovarian cancer.

M6A-mediated hsa_circ_0061179 inhibits DNA damage in ovarian cancer cells via miR-143-3p/TIMELESS.

Ovarian cancer (OC) is among the most common and deadly solid malignancies in women. Despite many advances in OC research, the incidence of OC continues to rise, and its pathogenesis remains largely unknown. Herein, we elucidated the function of hsa_circ_0061179 in OC. The levels of hsa_circ_0061179, miR-143-3p, TIMELESS, and DNA damage repair-related proteins in OC or normal ovarian tissues and cells were measured using real-time quantitative polymerase chain reaction and immunoblotting. The biological effects of hsa_circ_0061179 and miR-143-3p on proliferation, clone formation, DNA damage, and apoptosis of OC cells were detected by the cell counting kit-8 assay, 5-methylethyl-2'-deoxyuridine, flow cytometry, the comet assay, and immunofluorescence staining combined with the confocal microscopy. The interaction among hsa_circ_0061179, miR-143-3p, and TIMELESS was validated by the luciferase reporter assay. Mice tumor xenograft models were used to evaluate the influence of hsa_circ_0061179 on OC growth in vivo. We found that human OC biospecimens expressed higher levels of hsa_circ_0061179 and lower levels of miR-143-3p. Hsa_circ_0061179 was found to bind with miR-143-3p, which directly targets TIMELESS. Hsa_circ_0061179 knockdown or miR-143-3p overexpression suppressed the proliferation and clone formation of OC cells and increased DNA damage and apoptosis of OC cells via the miR-143-3p/TIMELESS axis. Furthermore, we demonstrated that METTL3 could direct the formation of has_circ_0061179 through a specific m6A modification site. YTHDC1 facilitated the cytoplasmic transfer of has_circ_0061179 by directly binding to the modified m6A site. Our findings suggest that hsa_circ_0061179 acts as the sponge of miR-143-3p to activate TIMELESS signaling and inhibits DNA damage and apoptosis in OC cells.

Research Advances in the Roles of N6-Methyladenosine Modification in Ovarian Cancer.

Ovarian cancer (OC) is the most lethal gynecological tumor, characterized by its insidious and frequently recurring metastatic progression. Owing to limited early screening methods, over 70% of OC cases are diagnosed at advanced stages, typically stage III or IV. Recently, N6-methyladenosine (m6A) modification has emerged as a hotspot of epigenetic research, representing a significant endogenous RNA modification in higher eukaryotes. Numerous studies have reported that m6A-related regulatory factors play pivotal roles in tumor development through diverse mechanisms. Moreover, recent studies have indicated the aberrant expression of multiple regulatory factors in OC. Therefore, this paper comprehensively reviews research advancements concerning m6A in OC, aiming to elucidate the regulatory mechanism of m6A-associated regulators on pivotal aspects, such as proliferation, invasion, metastasis, and drug resistance, in OC. Furthermore, it discusses the potential of m6A-associated regulators as early diagnostic markers and therapeutic targets, thus contributing to the diagnosis and treatment of OC.

Ovarian cancer (OC) presents a formidable challenge in the medical field, often detected at advanced stages, necessitating urgent exploration of diagnostic and therapeutic avenues. This review delves into the intricate role of N6-methyladenosine (m6A) RNA modification in OC, a dynamic epigenetic process increasingly recognized for its regulatory role in cancer biology. Highlighting recent advancements, the review sheds light on how m6A-related factors influence crucial aspects of OC progression, including tumor growth, metastasis, and resistance to treatment. Specifically, m6A methyltransferases, binding proteins, and demethylases exert multifaceted effects on OC progression, influencing the expression of pivotal oncogenes and tumor suppressors. While promising, translating these insights into effective therapies requires further investigation. By comprehensively understanding the influence of m6A on OC, there lies hope for developing improved diagnostic techniques and novel treatment strategies to combat this complex disease.

Encoding, working memory, or decision: how feedback modulates time perception.

The hypothesis that individuals can accurately represent temporal information within approximately 3 s is the premise of several theoretical models and empirical studies in the field of temporal processing. The significance of accurately representing time within 3 s and the universality of the overestimation contrast dramatically. To clarify whether this overestimation arises from an inability to accurately represent time or a response bias, we systematically examined whether feedback reduces overestimation at the 3 temporal processing stages of timing (encoding), working memory, and decisions proposed by the scalar timing model. Participants reproduced the time interval between 2 circles with or without feedback, while the electroencephalogram (EEG) was synchronously recorded. Behavioral results showed that feedback shortened reproduced times and significantly minimized overestimation. EEG results showed that feedback significantly decreased the amplitude of contingent negative variation (CNV) in the decision stage but did not modulate the CNV amplitude in the encoding stage or the P2-P3b amplitudes in the working memory stage. These results suggest that overestimation arises from response bias when individuals convert an accurate representation of time into behavior. Our study provides electrophysiological evidence to support the conception that short intervals under approximately 3 s can be accurately represented as "temporal gestalt."

Maternal intrapartum fever during epidural labour analgesia: Incidence and influencing factors.

BACKGROUND: The management and nursing care of women's temperature during delivery is an important part of clinical obstetrics. We aimed to evaluate maternal intrapartum fever during epidural labour analgesia to provide evidence for the management and care of women in labour. METHODS: This study was conducted and reported according to the STROBE statement. Women in labour undergoing epidural labour analgesia in our hospital from 1 January 2021 to 31 August 2022 were retrospectively selected. The characteristics of women in labour with and without intrapartum fever were compared. Pearson correlation and logistic regression analysis were used to analyse the influencing factors of postpartum fever. RESULTS: A total of 196 women in labour were included, the incidence of maternal intrapartum fever in women in labour undergoing epidural analgesia was 27.5%. Pearson correlation analyses showed that BMI, oxytocin use, labour duration, number of vaginal examinations, time from rupture of the foetal membranes to the end of labour and duration of epidural analgesia were all correlated with the occurrence of intrapartum fever (all P < 0.05). Logistic regression analyses indicated that body mass index ≥28 kg/m2 (OR = 1.825), oxytocin use (OR = 2.082), labour duration ≥9.2 h (OR = 2.613), number of vaginal examinations ≥8 (OR = 2.044-3.115), the time from rupture of the foetal membranes to the end of labour ≥250 min (OR = 2.766) and duration of epidural analgesia ≥300 min (OR = 3.106) were risk factors for intrapartum fever in women in labour undergoing epidural analgesia (all P < 0.05). CONCLUSIONS: Maternal intrapartum fever in women in labour undergoing epidural analgesia is common and influenced by many factors. Nurses should take early preventive care measures according to these factors during epidural analgesia in labour.

Electrophysiological evidence for a common magnitude representation of spatiotemporal information in working memory.

Spatiotemporal interference has attracted increasing attention because it provides a window for studying the neural representation of magnitude in the brain. We aimed to identify the neural basis of spatiotemporal interference using a Kappa effect task in which two circles were presented in sequence with two time intervals and three space distances. Participants reproduced the time intervals while ignoring the space distance when electroencephalogram signals were recorded synchronously. The behavior results showed that production time increased with time interval and space distance. Offset of the time intervals elicited typical P2 and P3b components. Larger parietal P2 and P3b amplitudes were elicited by the combination of longer time intervals and longer space distances. The parietal P2 and P3b amplitudes were positively correlated with the production time, and the corresponding neural source was located in the parietal cortex. The results suggest that the parietal P2 and P3b index updates a common representation of spatiotemporal information in working memory, which provides electrophysiological evidence for the mechanisms underlying spatiotemporal interferences. Our study supports a theory of magnitude, in which different dimensions can be integrated into a common magnitude representation in a generalized magnitude system that is localized at the parietal cortex.

Urinary phytoestrogens and the risk of uterine leiomyomata in US women.

BACKGROUND: Uterine leiomyomata (UL) is a common gynecological disease in women. Studied on the relationship between single metabolites of urinary phytoestrogens and UL, especially for the combined effects of mixed metabolites on UL still are insufficient. METHODS: In this cross-sectional study, we included 1,579 participants from the National Health and Nutrition Examination Survey. Urinary phytoestrogens were assessed by measuring urinary excretion of daidzein, genistein, equol, O-desmethylangolensin, enterodiol and enterolactone. The outcome was defined as UL. Weighted logistic regression was used to analyze the association between single metabolites of urinary phytoestrogens and UL. Notably, we adopted the weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), and quantile g-computation (qgcomp) models, to investigate the combined effects of six mixed metabolites on UL. RESULTS: The prevalence of UL was approximately 12.92%. After adjusting age, race/ethnicity, marital status, drinking status, body mass index, waist circumference, menopausal status, ovary removed status, use of female hormones, hormones/hormone modifiers, total energy, daidzein, genistein, O-desmethylangolensin, enterodiol, and enterolactone, the association of equol with UL was significant [Odds ratio (OR) = 1.92, 95% confidence interval (CI): 1.09-3.38]. In the WQS model, mixed metabolites of urinary phytoestrogen had a positive association with UL (OR = 1.68, 95%CI: 1.12-2.51), with the highest weighted chemical of equol. In the gpcomp model, equol had the largest positive weight, followed by genistein and enterodiol. In the BKMR model, equol and enterodiol have positive correlation on UL risk, while enterolactone has negative correlation. CONCLUSION: Our results implied a positive association between the mixed metabolites of urinary phytoestrogen and UL. This study provides evidence that urinary phytoestrogen-metabolite mixture was closely related to the risk of female UL.

LncRNA SOX21-AS1 accelerates endometrial carcinoma progression through the miR-7-5p/RAF1 pathway.

BACKGROUND: Endometrial carcinoma (EC) is one of the world's typical female reproductive tract malignancies, mostly occurring in postmenopausal women. Many reports have confirmed that long non-coding RNA SOX21 antisense RNA1 (lncRNA SOX21-AS1) is associated with the progressions of various cancer. However, the mechanism of SOX21-AS1 in EC remains unclear. Our study is intended to probe the mechanisms of SOX21-AS1 on EC progression. METHODS: The CCK-8 assay and colony formation detected cell proliferation. Cell migration and invasion were assessed by transwell analysis. Apoptosis was measured by flow cytometry assay. Bioinformatics software predicted target binding and confirmed using a luciferase reporter analysis. RESULTS: SOX21-AS1 expression was upregulated in EC tumor tissues and cells. High expression of SOX21-AS1 was associated with poor overall survival. Silencing of SOX21-AS1 restrained cell proliferation, migration, invasion, and increased apoptosis in HEC-1A and Ishikawa cells. Additionally, bioinformatics analysis demonstrated that SOX21-AS1 modulated RAF1 expression by competitively binding to miR-7-5p. Functionally, silencing of RAF1 reversed the functions of miR-7-5p inhibitor in the proliferation, invasion, and apoptosis of HEC-1A/sh-SOX21-AS1 and Ishikawa/sh-SOX21-AS1 cells. CONCLUSIONS: SOX21-AS1 promoted the pathological development of EC by regulating the miR-7-5p/RAF1 pathway. This research may provide a novel target for EC therapy.

Methylation-reprogrammed CHRM3 results in vascular dysfunction in the human umbilical vein following IVF-ET†.

Assisted reproductive technology (ART) has been used globally among infertile couples. However, many epidemiological investigations have indicated that ART is associated with a range of long-term adverse health outcomes in offspring, including cardiovascular disease, obesity, and increased plasma lipid levels. Until now, direct evidence has been limited regarding the pathological changes in vascular function in fetuses with ART. In this study, human umbilical cords were collected from healthy normal pregnancies and in vitro fertilization and embryo transfer (IVF-ET) pregnancies. Vascular functional studies involving acetylcholine (ACh), antagonists of its specific receptors, and L-type calcium channel/PKC-MLC20 phosphorylation pathway specific inhibitors were conducted. Quantitative real-time PCR, Western blotting, and methylation analyses were performed on umbilical vein samples. We found that the umbilical vein constriction induced by ACh in the IVF-ET group was significantly attenuated compared with that in the healthy normal pregnancy group, which was not only associated with the hypermethylation of ACh muscarinic receptor subtype 3 (CHRM3) and decreased expression of CHRM3, PKCß, and CaV1.2, but was also related to the reduced phosphorylation of MLC20. This study revealed that the hypermethylation of CHRM3, leading to a reduction in CHRM3 expression and downregulation of the CaV1.2/PKC-MLC20 phosphorylation pathway, was responsible for the decreased sensitivity to ACh observed in the umbilical vein under IVF-ET conditions. The hypermethylation of CHRM3 caused by IVF-ET might play an important role in altered vasoconstriction and impact cardiovascular systems in the long run.