AEBP1 upregulation contributes to cervical cancer progression by facilitating cell proliferation, migration, and invasion.

BACKGROUND: Aberrant expression of adipocyte enhancer-binding protein 1 (AEBP1) has been demonstrated to be involved in the tumorigenesis and progression of numerous cancers. This study was aimed to investigate the mechanism of AEBP1 in the development of cervical cancer. METHODS: The expression of AEBP1 in cervical cancer was assessed by immunohistochemistry. The function of AEBP1 on cell proliferation, migration, and invasion was determined by methyl thiazolyl tetrazolium assay, colony formation, and transwell assay. The activation of related signaling pathway was determined by western blot. The bioinformatics analysis was performed by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. RESULTS: Higher protein expression of AEBP1 was observed in patients with cervical cancer. Overexpressed AEBP1 promoted cell proliferation, migration, and invasion abilities in cervical cancer cells. Moreover, the research manifested that AEBP1 activated the phosphorylation of STAT3. GO and KEGG analysis showed that genes positively related to AEBP1 were highly enriched in functions like epithelial cell proliferation, muscle cell migration, myoblast migration, smooth muscle tissue development, ECM-receptor interaction, transcriptional misregulation in cancer, and proteoglycans in cancer. While genes negatively related to AEBP1 were associated with immunity, including inflammatory response, external-stimulus response, neutrophil, granulocyte, and macrophage chemotaxis. CONCLUSIONS: This study suggested that AEBP1 acts as an oncogened and might be a potential therapeutic target for the treatment of cervical cancer.

GLP1R boosts survival, migration and invasion of endometrial cancer cells and protects against ferroptotic cell death.

BACKGROUND: Despite the strong evidence concerning carcinogenic roles of glucagon-like peptide 1 receptor (GLP1R), the role of this gene in endometrial cancer (EC) remains elusive. This study investigated the properties of GLP1R on EC in vitro. METHODS: The expression of GLP1R in EC was detected by RT-qPCR, immunohistochemistry, and western blotting. Cell viability, cell cycle, apoptosis, migration, invasion and ferroptosis were assessed through CCK-8, flow cytometry, wound healing, transwell, DCFH-DA and western blotting, respectively. RESULTS: We found that GLP1R was up-regulated in EC than normal specimens. It had the highest expression in AN3CA cells. Cell viability, migration and invasion were significantly reduced, while cell cycle arrest and apoptosis were induced following GLP1R knockdown. The malignant biological behaviours of AN3CA cells were investigated when treated with exendin-4 (GLP1R agonist). Moreover, GLP1R lowered intracellular ROS level and expression of SLC7A11, and FTH1, but mitigated GPX4 expression in AN3CA cells. CONCLUSION: In a word, GLP1R was up-regulated in EC and its up-regulation facilitated the proliferative and metastatic potentials, and protected cells from ferroptosis, thereby accelerating EC progression. These data emphasised the potency of GLP1R as a therapeutic agent against EC.

Endometrial cancer (EC) is the second most common form of gynaecologic malignancy, with over 189,000 new cases and about 45,000 deaths worldwide per annum. The effects of glucagon-like peptide 1 receptor (GLP1R) in cancers such as colon and pancreatic cancers have been uncovered. However, whether GLP1R affects EC progression especially ferroptosis process remains elusive. In this study, up-regulation of GLP1R promotes the proliferative and metastatic potentials of EC cells, and protects EC cells from ferroptosis. The opposite results are observed in GLP1R knocking-down. Our study found that GLP1R may exert an oncogene function in EC cells, which can affect proliferative, migrated as well as invasive capacities of EC cells. Moreover, it protected EC cells from ferroptosis. Thus, our results expanded the understanding of the function of GLP1R protein and offered insights into the targeted treatment strategies against EC.

Effects of metalloprotease ADAMTS12 on cervical cancer cell phenotype and its potential mechanism.

ADAMTS12 is a gene widely expressed in human tissues. We studied the expression level of ADAMTS12 in cervical cancer tissue and its relationship with clinicopathological features. We also explored the function of ADAMTS12 in cervical cancer cells and its underlying mechanisms. We found the higher expression level of ADAMTS12 in cancer tissues, which was associated with the worse overall survival rate. The immunofluorescence assay showed that the cytoplasm of cervical cancer cells is the main expression site of ADAMTS12. Overexpression of ADAMTS12 in HeLa and CaSki cells prominently promoted the cell proliferation, migration and invasion. We found that 2032 genes were correlated with ADAMTS12, which was mainly related to extracellular matrix, TGF-ß signaling pathway. The phosphorylation levels of mTOR and 4E-BP1 were upregulated in ADAMTS12-overexpressing cells. Co-Immunoprecipitation combined with protein mass spectrometry showed that TGF-ß signaling pathway-related proteins interacting with ADAMTS12 were screened from HeLa cells with ADAMTS12 overexpression. Therefore, we concluded that ADAMTS12 may affect the mTOR signaling pathway through the interacting with TGF-ß1, and then affect the biological function of cervical cancer cells.

Suppressing electron-phonon coupling in organic photovoltaics for high-efficiency power conversion.

The nonradiative energy loss (∆Enr) is a critical factor to limit the efficiency of organic solar cells. Generally, strong electron-phonon coupling induced by molecular motion generates fast nonradiative decay and causes high ∆Enr. How to restrict molecular motion and achieve a low ∆Enr is a sticking point. Herein, the free volume ratio (FVR) is proposed as an indicator to evaluate molecular motion, providing new molecular design rationale to suppress nonradiative decay. Theoretical and experimental results indicate proper proliferation of alkyl side-chain can decrease FVR and restrict molecular motion, leading to reduced electron-phonon coupling while maintaining ideal nanomorphology. The reduced FVR and favorable morphology are simultaneously obtained in AQx-6 with pinpoint alkyl chain proliferation, achieving a high PCE of 18.6% with optimized VOC, JSC and FF. Our study discovered aggregation-state regulation is of great importance to the reduction of electron-phonon coupling, which paves the way to high-efficiency OSCs.

Paeonol ameliorates endometrial hyperplasia in mice via inhibiting PI3K/AKT pathway-related ferroptosis.

BACKGROUND: Paeonol (Pae) is one of the active ingredients from components of Guizhi Fuling Capsule, a traditional Chinese medicine widely used for the treatment of women's diseases, which exhibits various biological and pharmacological activities. PURPOSE: The objective of this study was to investigate the molecular mechanism underlying the role of Pae in protecting against endometrial hyperplasia (EH). METHODS: CCK-8 assay was performed to detect the effect of Pae on cell proliferation. Hematoxylin and eosin (H&E) staining was performed to evaluate uterine tissue structure. A network pharmacology study was performed to search the disease targets. Single-cell transcriptome analysis was performed with uterine tissues from 3 healthy donors and 3 EH patients on 10X Genomics platform. Changes in lipid peroxidation were detected by the MDA reaction. IHC assay, Western blot, immunofluorescence and RT-qPCR were used to study the effects of estradiol and Pae on the expression levels of GPX4, PI3K, AKT, p-PI3K, p-AKT in mice. RESULTS: Pae treatment resulted in a decrease in cell viability of endometrial epithelial cells. Loss of uterus weight and morphology changes were observed in mice. In addition, Fe iron concentration and MDA levels increased, while the expression of GPX4, p-PI3K and p-AKT diminished. CONCLUSIONS: Pae exhibited obvious alleviative activity in estradiol-induced mice via PI3K/AKT signaling pathway-regulated ferroptosis.

GLP1R inhibits the progression of endometrial carcinoma through activation of cAMP/PKA pathway.

BACKGROUND: This study strived to explore the role and mechanism of glucagon-like peptide-1 receptor (GLP1R) in endometrial carcinoma (EC). METHODS: In detail, after transfection of GLP1R overexpression vector and small interfering RNA targeting PKA, the mRNA expressions of GLP1R and PKA in EC cells (Ishikawa and RL95-2) were quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The cell biological behaviors, including proliferation, migration, invasion, and apoptosis, were detected using 5-ethynyl-2'-deoxyuridine (EdU), wound healing, transwell, and flow cytometry assays, respectively. The cyclic adenosine monophosphate (cAMP) content and related protein expressions (GLP1R, p-PKA, and PKA) were determined by enzyme-linked immunosorbent assay (ELISA) and western blot. The effects of GLP1R and PKA on tumorigenesis were evaluated by measuring the tumor volume and weight of mice bearing EC. RESULT: According to the results, GLP1R expression was downregulated in EC tissues and cells, and there was a positive correlation between GLP1R and PKA expressions. Upregulation of GLP1R promoted apoptosis and activated the cAMP/PKA signaling pathway in EC cells, while hindering the EC cell proliferation, invasion, migration, and the growth of tumor in mice. However, these effects were blunted by downregulation of PKA, which also accelerated the progression of EC in vitro and in vivo via inhibiting the activation of cAMP/PKA signaling pathway. CONCLUSION: Collectively, upregulation of GLP1R impeded EC progression via inducing the activation of cAMP/PKA signaling pathway, which may be a potential treatment for EC.

Analysis on clinical association of uterine scar diverticulum with subsequent infertility in patients underwent cesarean section.

ABSTRACT: To evaluate the relationship between uterine cesarean scar diverticulum (CSD) and subsequent infertility in patients who underwent cesarean section, and determine the effects of pelvic fluid-releasing inflammations on infertility.A retrospective analysis was designed among patients with CSD who were admitted to our hospital from January 1, 2018 to December 31, 2019. A total of 60 patients with CSD and uterine fibroids or benign ovarian tumors who underwent cesarean section were included, and divided into the CSD group and control group. Baseline characteristics of all patients were collected, and the pelvic adhesion scores and the percents of tubal patency were evaluated. Furthermore, the postoperative clinical outcomes were followed up. The levels of inflammatory factors in pelvic fluid were tested using Elisa kits.Preoperative data indicated that the size of the uterine scar diverticulum was (1.68 ±â€Š0.52) cm, the pelvic adhesion scores were higher in CSD group than control group (4.67 ±â€Š0.90 vs 0.47 ±â€Š0.90, P < .05), and 21 of 30 patients with unobstructed fallopian tubes. The levels of tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in patients with CSD were obviously higher than control group (P < .05). After the follow-up, the data displayed that no CSD was found in all patients, the time of menstrual period in patients with CSD was shortened to 7.80 ±â€Š1.27 days, and the myometrial thickness at uterine scar was significantly increased (P < .05). Additionally, the pregnancy rate was increased, and 12 of 30 patients were repregnant. Correlation analysis showed that the levels of inflammatory factors (tumor necrosis factor-α, interleukin-1ß, interleukin-6), the size of uterine scar diverticulum, and the myometrial thickness at uterine scar were significantly correlated with subsequent infertility (r = 0.307, 0.083, 0.147, 0.405, 0.291, P < .05).Uterine scar diverticulum repair could improve menstrual prolongation, increased the thickness of myometrium and repregnant rate. Subsequent infertility was positively correlated with uterine scar diverticulum and the levels of inflammatory factors.

Analysis of risk factors for cesarean scar diverticulum: A STROBE-compliant case-control study.

ABSTRACT: The purpose of this study was to explore the relevant factors that affect the risk of cesarean scar diverticulum (CSD).A retrospective, case-control study was designed among women with a history of cesarean section (CS) who were admitted in Zhejiang Tongde Hospital from January 2017 to December 2019. Women with missing information were excluded. The basic clinical characteristics and the risk factors for CSD were assessed using univariate analysis and multivariate logistic regression analysis.A total of 216 women were analyzed, including 87 patients with CSD and 129 cases without CSD as control. Significant differences in number of CS, trial of labor (elective or urgent CS), CS interval, uterine position, intraoperative hemorrhage, and dysmenorrhea between CSD group and control group (P < .05). Multivariate logistic regression analysis showed that number of CS, trial of labor, interval of CS, and uterine position were independent risk factors of CSD.In women with a history of CS, multiple cesarean deliveries, elective CS, cesarean interval of less than 5 years, and retroflexed position of the uterus may be associated with an elevated risk of CSD.

Guizhi Fuling Capsule ameliorates endometrial hyperplasia through promoting p62-Keap1-NRF2-mediated ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Guizhi Fuling Capsule (GFC) is a classical traditional Chinese medicine officially recorded in Synopsis of the Golden Chamber and has long been used to treat gynecological diseases in China. However, scientific evidence for the anti-endometrial hyperplasia potential of GFC used in traditional medicine is lacking. AIM OF THE STUDY: This study evaluated whether GFC protects against endometrial hyperplasia and its potential mechanism in mice. METHODS AND MATERIALS: We used estrogen (estradiol) to induce endometrial hyperplasia in mice. C57BL/6 mice were treated with estradiol subcutaneously for 21 days, and GFC (75 mg/kg and 150 mg/kg) was given intragastric administration from the first day of the modeling. H&E staining is used to evaluate endometrial tissue structure change. Malondialdehyde was measured to explore lipid peroxidation. Western blot, immunohistochemistry and immunofluorescence were performed to observe the expressions of GPX4, p62, Keap1 and NRF2. RESULTS: The degree of ferroptosis in endometrial tissue of patients with endometrial hyperplasia was lower than normal endometrial tissue. In addition, ferroptosis inducer imidazole ketone erastin could improve endometrial hyperplasia in mice. Interestingly, GFC significantly alleviated endometrial hyperplasia through triggering ferroptosis. Furthermore, GFC inhibited p62-Keap1-NRF2 pathway in estradiol-induced endometrial hyperplasia model. CONCLUSIONS: GFC may attenuate estrogen-induced endometrial hyperplasia in mice through triggering ferroptosis via inhibiting p62-Keap1-NRF2 pathway. These findings suggest that GFC might act as a promising traditional Chinese medicine to treat endometrial hyperplasia.

Curcumin analogue AI-44 alleviates MSU-induced gouty arthritis in mice via inhibiting cathepsin B-mediated NLRP3 inflammasome activation.

NOD-like receptors (NLRs), as a part of intracellular pattern recognition receptors (PRR), are important regulators in innate immune system. The NLRP3 inflammasome which is a member of NLRs has been linked to several human inflammatory diseases. Gouty arthritis is triggered when the deposition of monosodium urate (MSU) crystals in joints induces acute inflammation characterized by the recruitment of macrophages and neutrophils. In this study, we explored the curcumin analogue AI-44 alleviated the gouty arthritis in mice via suppressing MSU engaging NLRP3 inflammasome activation. Furthermore, we demonstrated that AI-44 inhibited the interaction of cathepsin B and NLRP3 to prevent the activation of NLRP3 inflammasome. Moreover, we found AI-44 inhibited the enzyme activity of cathepsin B and bound to the key residue E122 in cytoplasm but not in lysosome. Collectively, these data suggest that AI-44 is a novel drug candidate for the treatment of gouty arthritis through targeting cathepsin B and inhibiting NLRP3 inflammasome activation.

Laparoscopic repair with hysteroscopy of cesarean scar diverticulum.

AIM: The aim of this study was to investigate the clinical data of laparoscopic repair with hysteroscopy of cesarean scar diverticulum (CSD). METHODS: We retrospectively evaluated 49 patients with CSD in our hospital who had undergone laparoscopic repair with hysteroscopy from January 2014 to June 2015. All patients had a history of cesarean section deliveries and prolonged postmenstrual spotting (duration 16.1 ± 3.4 days). The diagnosis of CSD was established by using 2-D transvaginal ultrasound. RESULTS: All patients underwent the surgical repair successfully, without evident complications. The mean operation time was 90.4 ± 9.1 min, the mean volume of blood loss was 31.2 ± 14.3 mL, and the mean length of hospital stay was 4.1 ± 0.3 days. All patients were followed for 6 months after the operation; the mean duration of menstruation was 7.5 ± 2.5 days shorter on average than the pre-surgical menstrual days, and the difference was statistically significant (P = 0.001). According to the clinical symptoms assessment, 89.8% (44/49) of the surgeries were effective, while according to the anatomic assessment, 95.9% (47/49) were effective. CONCLUSION: Laparoscopic repair with hysteroscopy of CSD was confirmed to be a safe, effective, and minimally invasive treatment, and should be widely used to treat patients with CSD.

[Protective effects and its mechanism of lipoxins on human umbilical vein endothelial cells under hypoxia].

OBJECTIVE: To investigate protective effects and mechanisms of lipoxinA(4) (LXA(4)) on human umbilical vein endothelial cells (HUVEC) under hypoxia in vitro. METHODS: The HUVEC culture were divided into groups as followed: added M199 culture medium as normal control groups, added CoCl2 to mimic hypoxia in vitro as hypoxia group and added different concentrations of LXA(4) (1, 10, 100 nmol/L) were added to the induced hypoxial HUVEC as agents intervention group. Morphological changes of HUVEC were observed by using inverted phase contrast microscope. The influence of LXA(4) on cell survival was investigated by methyl thiazolyl tetrazolium (MTT) assaying method after the treatment with different concentrations of LXA(4) and 100 nmol/L lipoxinA(4) according to different time (4, 8, 12 and 24 hours). The expression of von-willebrand factor (vWF) was detected by immunocytochemistry method. The changes of cytosolic Ca(2+) were measured by laser scanning confocal microscope. RESULTS: (1) Morphological changes:the cells under hypoxia lost its normal shapes and showed necrosis, while the cells cocultured with 100 nmol/L LXA(4) were normal appropriately. (2) Survival rate: the survival rates of HUVEC under hypoxia was (40.1 +/- 3.9)% and increased to (52.9 +/- 1.4)%, (64.1 +/- 3.3)%, (76.6 +/- 1.6)% respectively when added with LXA(4) with concentration of 1, 10, 100 nmol/L into culture medium. There was significant different survival rate when compared with that of hypoxia group. (3) The level of vWF: The expression of vWF was decreased with the increasing concentrations of LXA(4) added into culture medium, the gray values were 203.9 +/- 0.7 in 1 nmol/L, 204.6 +/- 0.9 in 10 nmol/L, 191.8 +/- 0.5 in 100 nmol/L respectively, which reached statistical difference in comparison with that of hypoxia groups (P < 0.05). (4) Confocal analysis: the intracellular free Ca(2+) concentrations of HUVEC were intensified with LXA(4) treatment. CONCLUSIONS: LXA(4) plays an important role in keeping the normal shape of HUVEC under hypoxia, can enhance survival of hypoxial HUVEC and decrease the level of vWF in cytoplasm. The protective mechanism might be via decreasing mitochondria Ca(2+) overload and increasing cytoplasm Ca(2+) by nucleus Ca(2+) transference.

Effects of lipoxin A(4) on CoCl(2)-induced angiogenesis and its possible mechanisms in human umbilical vein endothelial cells.

Lipoxin A(4) (LXA(4)), a 'stop signal' for inflammation, is endogenously produced by eicosanoids, mainly via cell-to-cell interactions. At present, its influence on hypoxic angiogenesis, which is responsible for tumor growth and metastasis, has not been determined. Hypoxia regulates a variety of transcription factors including hypoxia-inducible factor (HIF)-1alpha, which plays a role in the expression of vascular endothelial growth factor (VEGF) and is considered a target for anti-angiogenic therapy. In this study, we utilized cobalt chloride (CoCl(2)) to mimic hypoxia in vitro. Data suggested that LXA(4) decreased the expression and nucleus translocation of HIF-1alpha in a dose-dependent manner in CoCl(2)-treated human umbilical vein endothelial cells (HUVEC). Furthermore, we confirmed that LXA(4) suppressed VEGF expression, tube formation and migration activity of HUVEC under hypoxia induced by CoCl(2). These results suggest that LXA(4) may have inhibitory effects on tumor angiogenesis through downregulation of the expression and nucleus translocation of HIF-1alpha. In summary, this study provides the first evidence for the anti-angiogenic role of LXA(4) on hypoxic human endothelial cells, which may have therapeutic value for cancer and other angiogenesis-associated diseases.

Formyl-peptide receptor like 1: a potent mediator of the Ca2+ release-activated Ca2+ current ICRAC.

In electrically non-excitable cells, one major source of Ca(2+) influx is through the store-operated (or Ca(2+) release-activated Ca(2+)) channel by which the process of emptying the intracellular Ca(2+) stores results in the activation of Ca(2+) channels in the plasma membrane. Using both whole-cell patch-clamp and Ca(2+) imaging technique, we describe the electrophysiology mechanism underlying formyl-peptide receptor like 1 (FPRL1) linked to intracellular Ca(2+) mobilization. The FPRL1 agonists induced Ca(2+) release from the endoplasmic reticulum and subsequently evoked I(CRAC)-like currents displaying fast inactivation in K562 erythroleukemia cells which expresses FPRL1, but had almost no effect in K562 cells treated with FPRL1 RNA-interference and HEK293 cells which showed no FPRL1 expression. The currents were impaired after either complete store depletion by the sarco/endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin, or after inhibition of PLC by U73122. Our results present the first evidence that FPRL1 is a potent mediator in the activation of CRAC channels.