The causal effect of reproductive factors on pelvic floor dysfunction: a Mendelian randomization study.

BACKGROUND: Pelvic floor dysfunction (PFD) is an extremely widespread urogynecologic disorder, the prevalence of which increases with aging. PFD has severely affected women's quality of life and has been called a social cancer. While previous studies have identified risk factors such as vaginal delivery and obesity for PFD, other reproductive factors, including age at menarche (AAMA), have been largely overlooked. Therefore, we used a Mendelian randomization (MR) study for the first time to investigate the potential causal relationship between reproductive factors and PFD. METHODS: We obtained summary statistics from genome-wide association studies (GWAS) for female genital prolapse (FGP), stress urinary incontinence (SUI), and five reproductive factors. Two-sample Mendelian randomization analysis (TSMR) was performed to explore the causal associations between these factors. The causal effects of reproductive factors on FGP and SUI were primarily estimated using the standard inverse variance weighting (IVW) method, with additional complementary and sensitivity analyses conducted using multiple approaches. A multivariate Mendelian randomization (MVMR) study was also conducted to adjust for pleiotropic effects and possible sources of selection bias and to identify independent exposure factors. RESULTS: Our findings revealed that advanced age at first sexual intercourse (AFS) and age at first birth (AFB) exhibited negative causal effects on both FGP and SUI. AAMA showed negative causal effects solely on FGP, while age at last live birth (ALB) and age at menopause (AAMO) did not demonstrate any causal effect on either FGP or SUI. And the MVMR results showed that AFB and AFS had independent negative causal effects on FGP and SUI, respectively. CONCLUSIONS: This study, for the first time, investigates the causal relationship between reproductive factors and PFD. The results suggested a causal relationship between some reproductive factors, such as AFB and AFS, and PFD, but there were significant differences between FGPand SUI. Therefore, future studies should explore the underlying mechanisms and develop preventive measures for reproductive factors to reduce the disease burden of PFD.

Mechanical stretching induces fibroblasts apoptosis through activating Piezo1 and then destroying actin cytoskeleton.

The anatomical positions of pelvic floor organs are maintained by ligaments and muscles. Stress urinary incontinence (SUI) occurs when the pelvic floor tissues are repeatedly stimulated by excessive mechanical tension that exceeds the bearing capacity of ligaments or muscles. Besides, cells respond mechanically to mechanical stimulation by reconstituting the Piezo1 and cytoskeletal system. The aim of this study is to determine how Piezo1 and actin cytoskeleton are involved in the mechanized stretch (MS) induced apoptosis of human anterior vaginal wall fibroblasts (hAVWFs) and the mechanism. A four-point bending device was used to provide mechanical stretching to establish a cellular mechanical damage model. The apoptosis of hAVWFs cells in non-SUI patients was significantly increased by MS, which exhibited apoptosis rates comparable to those of SUI patients. Based on these findings, Piezo1 connects the actin cytoskeleton to the apoptosis of hAVWFs cells, providing an idea for the clinical diagnosis and treatment of SUI. However, the disassembly of the actin cytoskeleton suppressed the protective effect of Piezo1 silencing on MS. Based on these findings, Piezo1 connects the actin cytoskeleton to apoptosis of hAVWFs, providing new insight for the clinical diagnosis and treatment of SUI.

Mechanical Stretching induces the apoptosis of parametrial ligament Fibroblasts via the Actin Cytoskeleton/Nr4a1 signalling pathway.

The anatomical positions of pelvic floor organs are maintained mainly by ligaments and muscles. Long-term excessive mechanical tension stimulation of pelvic floor tissue beyond the endurance of ligaments or muscles will lead to the occurrence of pelvic organ prolapse (POP). In addition, cytoskeletal reconstitution is a key process by which cells respond to mechanical stimulation. The aim of the present study was to investigate the protective effect of actin cytoskeleton to resist mechanical stretching (MS)-induced apoptosis in parametrial ligament fibroblasts (PLFs) and the underlying mechanisms. MS provided by a four­point bending device could significantly induce apoptosis of PLFs from non-POP patients, which exhibited an apoptosis rate close to that of PLFs from POP patients, and the apoptosis rate was higher following latrunculin A (Lat-A, a potent inhibitor of actin) treatment. In addition, Nr4a1 and Bax expression was increased while Bcl-2 and caspase-3 expression was clearly decreased after treatment with MS and Lat-A. However, the apoptosis induced by MS was reduced when the expression of Nr4a1 was downregulated by siRNA. These outcomes reveal a novel mechanism that links the actin cytoskeleton and apoptosis in PLFs by Nr4a1; this mechanism will provide insight into the clinical diagnosis and treatment of POP.

Effects of mechanical trauma on the differentiation and ArfGAP3 expression of C2C12 myoblast and mouse levator ani muscle.

INTRODUCTION AND HYPOTHESIS: Severe mechanical injury or inadequate repair of the levator ani muscle (LAM) is a key contributor to the development of pelvic floor dysfunction (PFD). We explored the effects of mechanical stress on myoblasts and LAM at the cellular and animal level and the possible mechanism of PFD induced by mechanical trauma. METHODS: A C2C12 cell mechanical injury model was established with a four-point bending device, and a LAM injury mouse model was established via vaginal distention and distal traction, a common way of simulating the birth injury. The cells were divided into control, 1333 µ strain for 4-h cyclic mechanical strain (CMS), 1333 µ strain for 8-h CMS, and 5333 µ strain for 4-h CMS groups. Mice were divided into control and injury groups. After treatment, mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) levels, indicators of oxidative damage, cell apoptosis, muscle and cell morphology, cell differentiation, and expression of adenosine diphosphate (ADP)-ribosylation factor GTPase activating protein 3 (ArfGAP3) were detected. RESULTS: 5333 µ strain for 4-h CMS loading could induce myoblast injury with a reduction of ΔΨm, increased ROS levels, aggravation of oxidative damage-associated proteins NADPH oxidase 2 (NOX2) and xanthine oxidase (XO), and an increased apoptosis rate of C2C12 cells. At the same time, the injury CMS loading can promote the differentiation of myoblasts and increase the expression of ArfGAP3, a factor regulating intracellular transport. Mechanical trauma could also lead to the oxidative damage of LAM, indicated by 8-hydroxy-2'-deoxyguanosine(8-OHdG), NOX2 and XO protein accumulation, and increase the expression of ArfGAP3 in LAM. CONCLUSIONS: Oxidative stress caused by mechanical trauma induces dysfunction and damage repairing of LAM and C2C12 myoblast, and ArfGAP3 may promote the repairing process.

Role of Jagged1/STAT3 signalling in platinum-resistant ovarian cancer.

Jagged1, the essential ligand of the Notch signalling pathway, is highly expressed in metastatic prostate cancer, and its high expression in breast cancer is linked to poor survival rates. However, the mechanism of Jagged1's involvement in platinum-resistant ovarian cancer has not been thoroughly elucidated to date. The purpose of the present study was to investigate the roles of Jagged1 in the platinum resistance of ovarian cancer and its possible mechanisms. Compared with a platinum responsive group of ovarian epithelial cell carcinomas, we found the positive staining intensity of Notch1, Notch2, Jagged1, STAT3 and Epithelial-mesenchymal transition (EMT) proteins were lower in a platinum-resistant group. The DDP-resistant ovarian cancer cell line (C13K) had a higher IC50 of DDP than its parental cell line (OV2008) (P < 0.05) and acquired an EMT phenotype and invasive characteristics. Inhibiting or knockdown of Jagged1 expression could not only reduce its capacity of migration and invasion but also reverse EMT and down-regulate the expression of serine 727-phosphorylated STAT3 (pS727) at the protein level but not total STAT3 or tyrosine 705-phosphorylated STAT3 (pY705) in C13K cells. Furthermore, it was found that crosstalk between the Jagged1/Notch and JAK/STAT3 signalling pathways were involved in Jagged1-promoting EMT in C13K cells. Experiments in vivo showed a reduced micrometastatic tumour burden in the lung, liver and spleen of mice implanted with C13K cells with knocked-down Jagged1 compared with mice implanted with control cells. All of these results demonstrate that Jagged1 can crosstalk with the JAK/STAT3 pathway, and they all cooperate to promote the aberrant occurrence of EMT, further reinforcing the abilities of invasion and migration of platinum-resistant ovarian cancer in vivo and in vitro.

Knockdown of Hypoxia-Inducible Factor 1α (HIF-1α) Promotes Autophagy and Inhibits Phosphatidylinositol 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) Signaling Pathway in Ovarian Cancer Cells.

BACKGROUND Ovarian cancer has the highest mortality rate among all female genital tumors because of its insidious onset and drug resistance. Hypoxia-inducible factor 1alpha (HIF-1alpha), one of the best-studied oncogenes, plays an important part in tumor adaptation to microenvironmental hypoxia and was found to be overexpressed in several malignancies, including ovarian cancer. Previous studies found that the effect of HIF-1alpha on cancers may be correlated with autophagy and some signaling pathways, such as PI3K/AKT/mTOR, in several tumors. However, the function and potential mechanism have not been clearly defined. MATERIAL AND METHODS The expression of HIF-1alpha in ovarian cancer tissues were detected by immunohistochemistry. HIF-1alpha was knocked down by siRNA transfection. Cell viability was examined by CCK8 and colony formation assay. Apoptosis and autophagy were detected with flow cytometry, transmission electron microscopy, and laser scanning confocal microscopy, respectively. The proteins related to autophagy and PI3K/AKT/mTOR were detected through Western blot analysis. RESULTS HIF-1alpha was expressed at higher levels in epithelial or metastatic ovarian cancer tissue than in normal fallopian tube tissue. When HIF-1alpha was knocked down by siRNA in A2780 and SKOV3 cells, the viability of ovarian cancer cells was weakened, but the apoptosis and autophagy were strengthened. Accordingly, autophagosome formation increased and the expression of autophagy-related proteins LC3 and P62 increased in HIF-1alpha knockdown cells. The PI3K/Akt/mTOR signaling pathway was also found to be inactivated in HIF-1alpha knockdown cells. CONCLUSIONS These findings show that knockdown of HIF-1alpha promoted autophagy and inhibited the PI3K/AKT/mTOR signaling pathway in ovarian cancer cells.

MTA1 promotes the invasion and migration of pancreatic cancer cells potentially through the HIF-α/VEGF pathway.

The metastasis-associated gene 1 (MTA1) has previously been recognized as an oncogene, and abnormal MTA1 expression has been related to progression of numerous cancer types to the metastasis stage. However, the function of MTA1 in the regulation of pancreatic cancer progression and metastasis remains unclear. Western blot analysis was adopted to determine the expression of MTA1 in pancreatic cancer tissues and corresponding near normal tissues. Steady clone with MTA1-overexpression and MTA1-inhibitionweregenerated via lentivirus technology in BxPc-3 cells. Transwell assay was carried out for detecting the invasion of pancreatic cancer cells. The migration activity was assessed using the wound scratch assay. The effect of MTA1 in pancreatic cancer was evaluated in the mice xenografts. Western blot analysis was employed to determine the expression of hypoxia inducible factor-α (HIF-α) and vascular endothelial growth factor (VEGF) in vitro and in vivo. We observed that MTA1 overexpression enhanced migration and invasion ability of pancreatic cancer cells in vitro and increased HIF-α and VEGF protein levels in vitro and in vivo. MTA1 inhibition had the opposite effects. MTA1 protein level was positively related to HIF-α and VEGF protein levels. These results indicated that MTA1 potentially promoted pancreatic cancer metastasis via HIF-α/VEGF pathway. This research supplies a new molecular mechanism for MTA1 in the pancreatic cancer progression and metastasis. MTA1 may be an effective therapy target in pancreatic cancer.

Protective role of Nrf2 against mechanical-stretch-induced apoptosis in mouse fibroblasts: a potential therapeutic target of mechanical-trauma-induced stress urinary incontinence.

INTRODUCTION AND HYPOTHESIS: We investigated the protective effect and underlying molecular mechanism of nuclear factor-E2-related factor 2 (Nrf2) against mechanical-stretch-induced apoptosis in mouse fibroblasts. METHODS: Normal cells, Nrf2 silencing cells, and Nrf2 overexpressing cells were respectively divided into two groups-nonintervention and cyclic mechanical strain (CMS)-subjected to CMS of 5333 µ (1.0 Hz for 4 h), six groups in total (control, CMS, shNfe212, shNfe212 + CMS, LV-shNfe212, and LV-shNfe212 + CMS). After treatment, cell apoptosis; cell-cycle distribution; expressions of Nrf2, Bax, Bcl-2, Cyt-C, caspase-3, caspase-9, cleaved-caspase-3, and cleaved-caspase-9; mitochondrial membrane potential (ΔΨm); reactive oxygen species (ROS); and malondialdehyde (MDA) levels were measured. Thirty virgin female C57BL/6 mice were divided into two groups: control (without intervention) and vaginal distension (VD) groups, which underwent VD for 1 h with an 8-mm dilator (0.3 ml saline). Leak-point pressure (LPP) was tested on day 7 after VD; Nrf2 expression, apoptosis, and MDA levels were then measured in urethra and anterior vaginal wall. RESULTS: Mechanical stretch decreased Nrf2 messenger RNA (mRNA) and protein expressions. Overexpression of Nrf2 alleviated mechanical-stretch-induced cell apoptosis; S-phase arrest of cell cycle; up-regulation of Bax, cytochrome C (Cyt-C), ROS, MDA, ratio of cleaved-caspase-3/caspase-3 and cleaved-caspase-9/caspase-9; and exacerbated the decrease of Bcl2 and ΔΨm in L929 cells. On the contrary, silencing of Nrf2 showed opposite effects. Besides, VD reduced LPP levels and Nrf2 expression and increased cell apoptosis and MDA generation in the urethra and anterior vaginal wall. CONCLUSIONS: Nrf2 exhibits a protective role against mechanical-stretch -induced apoptosis on mouse fibroblasts, which might indicate a potential therapeutic target of mechanical-trauma-induced stress urinary incontinence (SUI).

Effects of RSC96 Schwann Cell-Derived Exosomes on Proliferation, Senescence, and Apoptosis of Dorsal Root Ganglion Cells In Vitro.

BACKGROUND Stress urinary incontinence is a common condition in women and can be associated with peripheral nerve injury. Exosomes. derived from Schwann cells, can enhance the regeneration of axons of the peripheral nervous system. This study aimed to investigate the effects of RSC96 Schwann cell-derived exosomes in a novel in vitro model of dorsal root ganglion (DRG) cell injury induced by cyclic mechanical strain (CMS). MATERIAL AND METHODS RSC96 Schwann cells and DRG cells were cultured in vitro. CMS in DRG cells involved mechanical stretch trauma with 5333 µ strain. ExoQuick-TC polymer was used to precipitate exosomes from RSC96 Schwann cell culture medium and identified by nanoparticle tracking analysis, electron microscopy, and Western blot for detection of CD9 and tumor susceptibility gene 101 (Tsg101) protein. Cultured DRG cells were treated with RSC96 Schwann cell-derived exosomes, followed by measurement of cell viability, proliferation, senescence, and apoptosis using the cell counting kit-8 (CCK-8) assay, senescence-associated beta-galactosidase (SA-ß-gal) staining, and Hoechst 33258 (blue) fluorescence nucleic acid staining using flow cytometry. RESULTS Mechanical stretch with 5333 µ strain for 8 hours at 1 Hz decreased the activity of cultured DRG cells. RSC96 Schwann cell-derived exosomes promoted cell proliferation and significantly inhibited apoptosis and senescence of DRG cells following injury induced by CMS. CONCLUSIONS An in vitro model of DRG cell injury induced by CMS, showed that RSC96 Schwann cell-derived exosomes had a protective effect. The effects of Schwann cell-derived exosomes on peripheral nerve injury, including in stress urinary incontinence, require future in vivo studies.

Therapeutic Effects of Punicalagin Against Ovarian Carcinoma Cells in Association With ß-Catenin Signaling Inhibition.

AIM: The aim of this study was to investigate the effects of punicalagin, a polyphenol isolated from Punica granatum, on human A2780 ovarian cancer cells in vitro. METHODS: The viability of human A2780 ovarian cells was evaluated using Cell Counting Kit-8 assay. Cell cycle was detected with flow cytometry analysis. The protein expression levels of Bcl-2, Bax, ß-catenin, cyclin D1, survivin, tissue inhibitor of metalloproteinase (TIMP)-2, and TIMP-3 were measured using Western blot analysis. Matrix metalloproteinase (MMP)-2 and MMP-9 activity was determined with gelatin zymography. Wound healing assay was used to determine cell migration. RESULTS: Punicalagin inhibited the cell viability of A2780 cells in a dose- and time-dependent manner, and the cell cycle of A2780 cells was arrested in G1/S phase transition. The treatment also induced apoptosis as shown by the up-regulation of Bax and down-regulation of Bcl-2. On the other hand, punicalagin treatment increased the expressions of TIMP-2 and TIMP-3, decreased the activities of MMP-2 and MMP-9, and inhibited cell migration. In addition, the ß-catenin pathway was suppressed as shown by the down-regulations of ß-catenin and its downstream factors including cyclin D1 and survivin. CONCLUSIONS: Punicalagin may have cancer-chemopreventive as well as cancer-chemotherapeutic effects against human ovarian cancer in humans through the inhibition of ß-catenin signaling pathway.

Transvaginal genital fistula repair with insertion of Foley catheter via fistula tract.

AIM: Genital fistula is one of the most devastating injuries in women. Despite advances in medical care, it continues to be a distressing problem, and the success rate of repair surgery is still limited. We herein describe our experience with the surgical approach using Foley catheter to repair genital fistula after gynecological surgery. METHODS: We retrospectively reviewed 29 patients who had received genital fistula repair surgery with Foley catheter between October 2011 and December 2013. Based on traditional transvaginal genital fistula repair surgery, we inserted a Foley catheter into the bladder or intestine through the fistula opening. As a result, the fistula opening could be tracked, which allows for a clear view to improve fistula repair. All 29 patients were followed up at 1, 4, and 12 weeks postoperatively. RESULTS: Of the 29 patients, 28 had successful surgical outcome (96.55% success rate). The mean operative time was 85 ± 8.1 min. The mean blood loss was 109 ± 23.4 mL. No intraoperative complications were observed. The mean postoperative hospitalization time was 10 ± 2.8 days. The follow-up rate was 100%. CONCLUSIONS: Repair of transvaginal genital fistula using Foley catheter had a high success rate, short operative time, minimal blood loss, low morbidity and short hospital stay. Therefore, this approach is minimally invasive and effective.

[Effect of mechanical stress on human parametrial ligament fibroblasts apoptosis].

OBJECTIVE: To explore the possible mechanism of mechanical factors in the pathogenesis of pelvic organ prolapse (POP). METHODS: The experiment material were uterosacral ligament and cardinal ligament- derived fibroblast from 10 patients who received total hysterectomy due to benign disease except POP. Fibroblast were cultured after collagenase digestion and identified by morphology and immocytochemical methods. Fibroblasts of 4-8 generations were stretched by four-point bending system for 0µ (0 mm), 1 333 µ (1 mm), 2 666 µ (2 mm), 5 333 µ (4 mm) strain, using 0 mm strain as the control group. Parameters was set to a frequency of 0.1 Hz, 4 hours. Cell apoptosis was tested by flow cytometry. RESULTS: Mechanical strain increased cell apoptosis [0 µ: (7.4 ± 1.5)%, 1 333 µ: (8.7 ± 2.2)%, 2 666 µ: (19.4 ± 3.4)%, 5333 µ: (50.9 ± 6.6)%, respectively]. Cell apoptosis rate was significantly higher under strong mechanical strain (2 666 µ and 5 333 µ versus 0 µ, all P < 0.05). CONCLUSION: Increased mechanical stress loading on human parametrial ligament fibroblasts could raise the rate of apoptosis.

Novel LncRNA LINC02936 Suppresses Ferroptosis and Promotes Tumor Progression by Interacting with SIX1/CP Axis in Endometrial Cancer.

Endometrial cancer (EC) is a prevalent gynecological malignancy, and metabolic disorders are among its most significant risk factors. Abnormal iron metabolism is associated with the progression of cancer malignancy. Nevertheless, the involvement of iron metabolism in the EC remains uncertain. Ceruloplasmin (CP) functions as a multicopper oxidase and ferroxidase, playing a crucial role in maintaining the metabolic balance between copper and iron. Prior research has demonstrated that the dysregulated expression of CP has important clinical implications in EC. However, ​the specific underlying molecular mechanisms remains uncertain. This research examined the impact of CP on the malignant advancement of EC by suppressing ferroptosis. Next, we explored the possibility that Long non-coding RNA (lncRNA) LINC02936/SIX1/CP axis may be a key pathway for inhibiting ferroptosis and promoting cancer progression in EC. Mechanistically, SIX1 modulates the expression of CP, whereas LINC02936 interacts with SIX1 and recruits SIX1 to the CP promoter, leading to upregulation of CP, inhibition of ferroptosis, and promotion of EC progression. Administration of a small peptide cloud block the LINC02936-SIX1 interaction, thereby inhibits EC progression by promoting ferroptosis. Altogether, this is the first report on the lncRNA regulation of ferroptosis in EC. Our research enhances the knowledge of the lncRNA-mediated regulation of ferroptosis in EC progression and indicates the potential therapeutic significance of the LINC02936/SIX1/CP axis in treating EC.

Tumor immunity: A brief overview of tumor­infiltrating immune cells and research advances into tumor­infiltrating lymphocytes in gynecological malignancies (Review).

Tumor immunity is a promising topic in the area of cancer therapy. The 'soil' function of the tumor microenvironment (TME) for tumor growth has attracted wide attention from scientists. Tumor-infiltrating immune cells in the TME, especially the tumor-infiltrating lymphocytes (TILs), serve a key role in cancer. Firstly, relevant literature was searched in the PubMed and Web of Science databases with the following key words: 'Tumor microenvironment'; 'TME'; 'tumor-infiltrating immunity cells'; 'gynecologic malignancies'; 'the adoptive cell therapy (ACT) of TILs'; and 'TIL-ACT' (https://pubmed.ncbi.nlm.nih.gov/). According to the title and abstract of the articles, relevant items were screened out in the preliminary screening. The most relevant selected items were of two types: All kinds of tumor-infiltrating immune cells; and advanced research on TILs in gynecological malignancies. The results showed that the subsets of TILs were various and complex, while each subpopulation influenced each other and their effects on tumor prognosis were diverse. Moreover, the related research and clinical trials on TILs were mostly concentrated in melanoma and breast cancer, but relatively few focused on gynecological tumors. In conclusion, the present review summarized the biological classification of TILs and the mechanisms of their involvement in the regulation of the immune microenvironment, and subsequently analyzed the development of tumor immunotherapy for TILs. Collectively, the present review provides ideas for the current treatment dilemma of gynecological tumor immune checkpoints, such as adverse reactions, safety, personal specificity and efficacy.

Inhibition of ACSS2 triggers glycolysis inhibition and nuclear translocation to activate SIRT1/ATG5/ATG2B deacetylation axis, promoting autophagy and reducing malignancy and chemoresistance in ovarian cancer.

BACKGROUND: Metabolic reprogramming is a hallmark of cancer, characterized by a high dependence on glycolysis and an enhanced utilization of acetate as an alternative carbon source. ACSS2 is a critical regulator of acetate metabolism, playing a significant role in the development and progression of various malignancies. ACSS2 facilitates the conversion of acetate to acetyl-CoA, which participates in multiple metabolic pathways and functions as an epigenetic regulator of protein acetylation, thereby modulating key cellular processes such as autophagy. However, the roles and intrinsic connections of ACSS2, glycolysis, protein acetylation, and autophagy in ovarian cancer (OC) remain to be elucidated. BASIC PROCEDURES: Utilizing clinical specimens and online databases, we analysed the expression of ACSS2 in OC and its relationship with clinical prognosis. By knocking down ACSS2, we evaluated its effects on the malignant phenotype, acetate metabolism, glycolysis, and autophagy. The metabolic alterations in OC cells were comprehensively analysed using Seahorse assays, transmission electron microscopy, membrane potential measurements, and stable-isotope labeling techniques. CUT&TAG and co-immunoprecipitation techniques were employed to explore the deacetylation of autophagy-related proteins mediated by ACSS2 via SIRT1. Additionally, through molecular docking, transcriptome sequencing, and metabolomics analyses, we validated the pharmacological effects of paeonol on ACSS2 and the glycolytic process in OC cells. Finally, both in vitro and in vivo experiments were performed to investigate the impact of paeonol on autophagy and its anti-OC effects mediated through the ACSS2/SIRT1 deacetylation axis. MAIN FINDINGS: ACSS2 is significantly upregulated in OC and is associated with poor prognosis. Knockdown of ACSS2 inhibits OC cells proliferation, migration, invasion, angiogenesis, and platinum resistance, while reducing tumour burden in vivo. Mechanistically, inhibiting ACSS2 reduces acetate metabolism and suppresses glycolysis by targeting HXK2. This glycolytic reduction promotes the translocation of ACSS2 from the cytoplasm to the nucleus, leading to increased expression of the deacetylase SIRT1. SIRT1 mediates the deacetylation of autophagy-related proteins, such as ATG5 and ATG2B, thereby significantly activating autophagy in OC cells and exerting antitumor effects. Paeonol inhibits acetate metabolism and glycolysis in OC cells by targeting ACSS2. Paeonol activates autophagy through the ACSS2/SIRT1/ATG5/ATG2B deacetylation axis, demonstrating inhibition of OC in vitro and in vivo. PRINCIPAL CONCLUSIONS: Pae can serve as an effective, low-toxicity, multi-targeted drug targeting ACSS2 and glycolysis. It activates autophagy through the ACSS2/SIRT1/ATG5/ATG2B deacetylation signalling cascade, thereby exerting anti-OC effects. Our study provides new insights into the malignant mechanisms of OC and offers a novel strategy for its treatment.

How does hypoxia inducible factor-1α participate in enhancing the glycolysis activity in cervical cancer?

The objective of this study is to explore the role of hypoxia inducible factor-1 (HIF-1) in glycolysis activity and its relationship with malignant biologic behaviors of cervical cancer. Immunohistochemistry was performed to study the protein expression and distribution of HIF-1α and glucose transport protein 1 (GLUT1) in cervical tissue of 158 cases, including 28 with normal cervical epithelium, 32 with cervical intraepithelial neoplasia, and 98 with invasive cervical cancer. Cobalt(II) chloride was used to induce hypoxia in Hela and Siha cells; the biologic behaviors of cells cultured in normal or hypoxic environments were monitored by colorimetric, Transwell, flow cytometry, and enzyme-linked immunosorbent assay; immunocytochemistry, Western blot, and reverse transcription-polymerase chain reaction were used to observe gene and protein expression of HIF-1α, GLUT1, and hexokinase II in cell lines during normoxia and hypoxia. The expression of HIF-1α and GLUT1 gradually increased from normal cervical tissue to cervical intraepithelial neoplasia, then to cervical cancer. There were significant differences among these groups (P < .05). HIF-1α was strongly associated with pathologic differentiation, clinic stage, magnitude of lesions, and patient age, whereas GLUT1 was associated with lymphatic metastasis (P < .05). HIF-1α was strongly associated with expression of GLUT1 (P < .05). In hypoxia, proliferation, invasion, resistance to apoptosis, and glycolysis of both Hela and Siha were enhanced compared with cells in normoxia (P < .05). Both gene and protein expressions of GLUT1 and hexokinase II were strengthened, whereas only the protein expression of HIF-1α was stronger in hypoxia than that in normoxia (P < .05). The results of Hela in normoxia and in hypoxia were similar to those of Siha (P > .05). HIF-1α plays a key role in cervical cancer both in vivo and in vitro. The role of HIF-1α can be implemented mainly by up-regulating its downstream gene, such as GLUT1, and the main mechanism may enhance glycolytic ability. Strong up-regulation and the role of HIF-1α suggest that HIF-1α could be an important factor in the onset and progression of cervical cancer and could be an attractive therapeutic molecular target for that type of cancer.

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.

Integrated analysis of single-cell RNA-seq and bulk RNA-seq unveils heterogeneity and establishes a novel signature for prognosis and tumor immune microenvironment in ovarian cancer.

Ovarian cancer is a highly heterogeneous gynecological malignancy that seriously affects the survival and prognosis of female patients. Single-cell sequencing and transcriptome analysis can effectively characterize tumor heterogeneity to better study the mechanism of occurrence and development. In this study, we identified differentially expressed genes with different differentiation outcomes of tumor cells by analyzing a single-cell dataset. Based on the differentially expressed genes, we explored the differences in function and tumor microenvironment among clusters via consensus clustering. Meanwhile, WGCNA was employed to obtain key genes related to ovarian cancer. On the basis of the TCGA and GEO datasets, we constructed a risk model consisting of 7 genes using the LASSO regression model, and successfully verified that the model was characterized as an independent prognostic factor, efficiently predicting the survival prognosis of patients. In addition, immune signature analysis showed that patients in the high-risk group exhibited lower anti-tumor immune cell infiltration and immunosuppressive status, and had poorer responsiveness to chemotherapeutic drugs and immunotherapy. In conclusion, our study provided a 7-gene prognostic model based on the heterogeneity of OC cells for ovarian cancer patients, which could effectively predict the prognosis of patients and identify the immune microenvironment status of patients.

HOXA1 promotes aerobic glycolysis and cancer progression in cervical cancer.

As a hallmark for cancer, aerobic glycolysis, also known as the Warburg effect contributes to tumor progression. However, the roles of aerobic glycolysis on cervical cancer remain elusive. In this work, we identified transcription factor HOXA1 as a novel regulator of aerobic glycolysis. High expression of HOXA1 is closely associated with poor outcome of patients. And, altered HOXA1 expression enhance or reduce aerobic glycolysis and progression in cervical cancer. Mechanistically, HOXA1 directly regulates the transcriptional activity of ENO1 and PGK1, thus induce glycolysis and promote cancer progression. Moreover, therapeutic knockdown of HOXA1 results in reduce aerobic glycolysis and inhibits cervical cancer progression in vivo and in vitro. In conclusion, these data indicate a therapeutic role of HOXA1 inhibits aerobic glycolysis and cervical cancer progression.

Gene signature of m6A-related targets to predict prognosis and immunotherapy response in ovarian cancer.

PURPOSE: The aim of the study was to construct a risk score model based on m6A-related targets to predict overall survival and immunotherapy response in ovarian cancer. METHODS: The gene expression profiles of 24 m6A regulators were extracted. Survival analysis screened 9 prognostic m6A regulators. Next, consensus clustering analysis was applied to identify clusters of ovarian cancer patients. Furthermore, 47 phenotype-related differentially expressed genes, strongly correlated with 9 prognostic m6A regulators, were screened and subjected to univariate and the least absolute shrinkage and selection operator (LASSO) Cox regression. Ultimately, a nomogram was constructed which presented a strong ability to predict overall survival in ovarian cancer. RESULTS: CBLL1, FTO, HNRNPC, METTL3, METTL14, WTAP, ZC3H13, RBM15B and YTHDC2 were associated with worse overall survival (OS) in ovarian cancer. Three m6A clusters were identified, which were highly consistent with the three immune phenotypes. What is more, a risk model based on seven m6A-related targets was constructed with distinct prognosis. In addition, the low-risk group is the best candidate population for immunotherapy. CONCLUSION: We comprehensively analyzed the m6A modification landscape of ovarian cancer and detected seven m6A-related targets as an independent prognostic biomarker for predicting survival. Furthermore, we divided patients into high- and low-risk groups with distinct prognosis and select the optimum population which may benefit from immunotherapy and constructed a nomogram to precisely predict ovarian cancer patients' survival time and visualize the prediction results.