Targeting JUNB to modulate M2 macrophage polarization in preeclampsia.

Preeclampsia (PE) is a complex disorder affecting pregnant women, leading to significant maternal and fetal morbidity and mortality. Understanding the cellular dynamics and molecular mechanisms underlying PE is crucial for developing effective therapeutic strategies. This study utilized single-cell RNA sequencing (scRNA-seq) to delineate the cellular landscape of the placenta in PE, identifying 11 distinct cell subpopulations, with macrophages playing a pivotal role in mediating cell-cell communication. Specifically, the transcription factor JUNB was found to be a key gene in macrophages from PE samples, influencing the interaction between macrophages and both epithelial and endothelial cells. Functional experiments indicated that interference with JUNB expression promoted macrophage polarization towards an M2 phenotype, which facilitated trophoblast invasion, migration, and angiogenesis. Mechanistically, JUNB regulated the MIIP/PI3K/AKT pathway, as evidenced by gene expression analysis following JUNB knockdown. The study further demonstrated that targeting JUNB could activate the PI3K/AKT pathway by transcriptionally activating MIIP, thus promoting M2 polarization and potentially delaying the onset of PE. These findings present new insights into the pathogenesis of PE and suggest a novel therapeutic approach by modulating macrophage polarization.

Preeclampsia in pregnant women with polycystic ovary syndrome: risk factor analysis based on a retrospective cohort study.

OBJECTIVES: To compare the clinical characteristics of pregnant women with polycystic ovary syndrome (PCOS) and perinatal outcomes with or without preeclampsia (PE) and to factors that are potentially associated with the onset of PE. MATERIAL AND METHODS: This was a retrospective study of pregnant women diagnosed with PCOS from January 2017 to December 2021. Eligible patients were divided into two groups based on the presence or absence of preeclampsia: a PE group and a non-PE group. Demographics, clinical characteristics, maternal and perinatal outcomes, and potential factors linked to disease recurrence were analyzed. RESULTS: In total, 616 patients were enrolled and respectively classified into the PE group (n = 51) and the non-PE group (n = 565). The incidence of PE in pregnant women with PCOS was 8.28%; this was significantly higher than that in non-PCOS pregnant women (3.22%, p < 0.001). Logistic regression analysis of the predictive factors for PE in women with PCOS revealed that the combination of maternal hyperandrogenism, a pre-pregnancy BMI ≥ 24 kg/m², and a family history of cardiovascular disease (CVD) and assisted reproductive techniques (ART) exhibited the steepest receiver-operating characteristic (ROC) curve value at 0.797 [95% confidence interval (CI): 0.733-0.862]. CONCLUSIONS: Patients with PCOS have a higher incidence of PE. We identified a series of significant and independent factors associated with PE in PCOS: maternal hyperandrogenism, a pre-pregnancy BMI ≥ 24 kg/m², and a family history of CVD and ART.

The role of ferritin and iron dextran in exacerbating preeclampsia in an L-NAME-treated rat model.

Background: Preeclampsia (PE) occurs in the second half of pregnancy and contributes to maternal and perinatal morbidity and mortality. Ferritin plays a key role in pregnancy, but the underlying mechanisms of its involvement in PE remain elusive. This study aimed to investigate the effects of ferritin concentrations and ferroptosis levels on PE rats at different stages of pregnancy. Methods: A PE rat model was established by administering nitro-L-arginine methyl ester (L-NAME; 60 mg/kg/day, orally) between the 13th and 19th days of pregnancy. Iron dextran (ID) was used to induce ferroptosis, whereas deferoxamine (DFO) was used to prevent ferroptosis. Pathological changes in the placenta and vascular system were observed by hematoxylin and eosin (H&E) staining. Oxidative stress levels, blood pressure, and urine protein levels were assessed. Inflammatory cytokines and cellular ferritin (FER)-related proteins were measured by enzyme-linked immunosorbent assay (ELISA). Western blot was performed to assess apoptosis- and ferroptosis-related proteins. Results: The data showed that L-NAME elevated blood pressure and urine protein levels in pregnant rats, while treatment with DFO-late and ID-early reduced them. Placental and vascular damage were ameliorated, and the levels of nitric oxide (NO), nitric oxide synthase (NOS), and superoxide dismutase (SOD) were increased. In contrast, the generation of reactive oxygen species (ROS), malonaldehyde (MDA), inflammatory factors, and FER-related proteins were suppressed, accompanied by reduced apoptosis- and increased ferroptosis-related proteins in the DFO-late group. Conclusions: Our results suggested that decreased ferritin levels in early pregnancy or elevated ferritin levels in late pregnancy in an L-NAME-treated rat model accelerated ferroptosis and exacerbated PE symptoms.

HPV16 E6-Activated OCT4 Promotes Cervical Cancer Progression by Suppressing p53 Expression via Co-Repressor NCOR1.

Human papillomaviruses (HPV), mainly HPV16 and HPV18, of high-risk classification are involved in cervical cancer carcinogenesis and progression. Octamer-binding transcription factor 4 (OCT4) is a key transcription factor that is increased in various cancer types. Cervical cancer patients with higher levels of OCT4 had worse survival rates. However, the definite mechanisms underlying its function in the development of cervical cancer still remain to be explicated. Here, our study demonstrated that OCT4 expression was slightly increased in cervical cancer tissues than in precancerous ones. However, OCT4 was significantly upregulated in HPV16-positive tissues, in contrast to the expression profiling for p53. Moreover, knockdown of HPV16 E6 in SiHa cells suppressed the expression of OCT4 with impaired activities of cell proliferation, migration, and invasion, while it recovered the expression of p53. Overexpression of OCT4 and p53 exerted opposite roles on cell proliferation, migration, invasion, and colony formation of cervical cancer cells. More importantly, the enforced expression of OCT4 augmented p53-inhibited cell migration, invasion, and colony formation in human cervical cancer by promoting EMT. Finally, we identified that OCT4 could bind to the p53 promoter region to repress p53 expression by recruiting co-repressor NCOR1 using luciferase, ChIP, and co-IP experiments. We further illustrated that OCT4 not only increased the lung metastasis of cervical cancer but also effectively reversed p53-inhibited lung metastasis. In conclusion, our results suggested that HPV16 E6 activated the expression of OCT4 and subsequently crippled the transcription of p53 via co-repressor NCOR1, which contributed to cervical cancer progression.

HDAC5 inactivates CYR61-regulated CD31/mTOR axis to prevent the occurrence of preeclampsia.

Our study was to pinpoint the significance of histone deacetylase 5 (HDAC5) affecting the pathogenesis of preeclampsia (PE) via CD31/mammalian target of rapamycin (mTOR) axis by regulating cysteine-rich angiogenic inducer 61 (CYR61). Expression of HDAC5, CYR61, and CD31/mTOR in placental tissues of patients with PE and trophoblast cells HTR-8/SVneo cells was determined first followed by their interaction analysis. Following different transfection, the significance of HDAC5 in cell functions was assayed in relation to CYR61 and CD31/mTOR. An in vivo PE mouse model was constructed for further validation. The clinical tissue and in vitro cell experimentations discovered that HDAC5 was downregulated in placental tissues of PE patients and trophoblast cells, while CYR61, CD31, mTOR, and p-mTOR displayed upregulation. After overexpression of HDAC5, trophoblast cell functions were enhanced. HDAC5 reduced the acetylation enrichment of H3K27 to inhibit the expression of CYR61. Furthermore, CYR61 promoted the activation of CD31/mTOR axis, thereby inhibiting HTR-8/SVneo cell functions. The in vivo rat model confirmed the above alterations. Taken together, HDAC5 contributes to downregulation of CYR61 through histone deacetylation, inactivating CD31/mTOR axis, which prevents the occurrence and development of PE.

Engineered Exosomes-Mediated Transfer of hsa-miR-320a Overcomes Chemoresistance in Cervical Cancer Cells via Targeting MCL1.

In cervical cancer (CC), cisplatin resistance greatly restricts the application in clinical. Here, we report that engineered exosomes-mediated transfer of hsa-miR-320a overcomes chemoresistance in cervical cancer cells via targeting Myeloid Cell Leukemia Sequence 1 (MCL1). In DDP resistant CC tissues, as well as cell lines, it was found that miR-320a expression is lower, engineered miR-320a exosomes were used to attenuate DDP resistance in Hela/DDP and Caski/DDP cells. Mechanistically, we find that MCL1, which is a target of miR-320a, overcomes DDP resistance in Hela/DDP cells and in mice. In conclusion, we report that the engineered miR-320a exosomes is proved to be effective and safe.

Subtyping of Human Papillomavirus-Positive Cervical Cancers Based on the Expression Profiles of 50 Genes.

Background: Human papillomavirus-positive (HPV+) cervical cancers are highly heterogeneous in molecular and clinical features. However, the molecular classification of HPV+ cervical cancers remains insufficiently unexplored. Methods: Based on the expression profiles of 50 genes having the largest expression variations across the HPV+ cervical cancers in the TCGA-CESC dataset, we hierarchically clustered HPV+ cervical cancers to identify new subtypes. We further characterized molecular, phenotypic, and clinical features of these subtypes. Results: We identified two subtypes of HPV+ cervical cancers, namely HPV+G1 and HPV+G2. We demonstrated that this classification method was reproducible in two validation sets. Compared to HPV+G2, HPV+G1 displayed significantly higher immune infiltration level and stromal content, lower tumor purity, lower stemness scores and intratumor heterogeneity (ITH) scores, higher level of genomic instability, lower DNA methylation level, as well as better disease-free survival prognosis. The multivariate survival analysis suggests that the disease-free survival difference between both subtypes is independent of confounding variables, such as immune signature, stemness, and ITH. Pathway and gene ontology analysis confirmed the more active tumor immune microenvironment in HPV+G1 versus HPV+G2. Conclusions: HPV+ cervical cancers can be classified into two subtypes based on the expression profiles of the 50 genes with the largest expression variations across the HPV+ cervical cancers. Both subtypes have significantly different molecular, phenotypic, and clinical features. This new subtyping method captures the comprehensive heterogeneity in molecular and clinical characteristics of HPV+ cervical cancers and provides potential clinical implications for the diagnosis and treatment of this disease.

Predictive factors associated with disease recurrence in patients with severe intrahepatic cholestasis of pregnancy: a retrospective study of 118 cases.

PURPOSE: To compare the clinical characteristics of pregnant women and perinatal outcomes with or without recurrent severe intrahepatic cholestasis of pregnancy (sICP), and identify possible factors associated with disease recurrence. METHODS: A retrospective study of 164,603 deliveries was performed to identify pregnant women diagnosed with sICP in the previous pregnancy from January 2012 to December 2020. Eligible patients were divided into two subgroups according to the status of disease recurrence in the second pregnancy: recurrent severe ICP (r-sICP) and non-recurrent severe ICP (nr-sICP). Demographics, clinical characteristics, maternal and perinatal outcomes, and potential factors linked to disease recurrence were analyzed. RESULTS: Totally 118 patients were enrolled and respectively classified into the r-sICP group (n = 63) and the nr-sICP group (n = 55). The proportion of hepatitis B virus (HBV) infection (HBsAg+, HBeAg+, HBcAb+) and early-onset ICP (<28 weeks) in the r-sICP group in the previous pregnancy were higher than those in the nr-sICP group. In the second delivery, neonatal outcomes in the r-sICP group were worse than those in the nr-sICP group. Logistic regression analysis of predictive factors for disease recurrence in the second delivery revealed that the combination of HBV infection and early-onset ICP in the previous delivery had the steepest receiver-operating characteristic (ROC) curve value 0.720 (95%CI: 0.629-0.812). CONCLUSION: Patients with sICP displayed a higher recurrence rate in the second pregnancy. Being <28 weeks at the time of ICP diagnosis and having HBV infection in the previous delivery appear to be independent predictive factors for disease recurrence of sICP.

MicroRNAs derived from urinary exosomes act as novel biomarkers in the diagnosis of intrahepatic cholestasis of pregnancy.

We aimed to investigate the value of cholestasis-related miRNAs in the diagnosis of intra-hepatic cholestasis of pregnancy (ICP) as well as the molecular mechanisms underlying the role of these miRNAs in the pathogenesis of ICP. In this study, electron microscopy was utilized to observe the exosomes present in the urine samples collected from both ICP patients and healthy pregnant women. Real-time PCR and area under curve (AUC) analysis were performed to predict the values of several miRNAs in the diagnosis of ICP. Bioinformatics analysis and luciferase assays were conducted to identify the target genes of miR-21, miR-29a and miR-590-3p, whose regulatory relationships were then established using real-time PCR, immunohistochemistry (IHC) assay and Western Blot. In the exosomes isolated from urine samples, several miRNAs, including miR-21, miR-29a and miR-590-3p, were differentially expressed between ICP patients and healthy pregnant women. In addition, the gene of intercellular adhesion molecule 1 (ICAM1) was identified as a shared target of miR-21, miR-29a and miR-590-3p, all of which inhibited ICAM1 expression. Therefore, up-regulated expression of miR-21, miR-29a and miR-590-3p in urinary exosomes reduced the expression of ICAM1, which in turn increased the incidence of ICP.

Protective effects of apigenin on LPS-induced endometritis via activating Nrf2 signaling pathway.

Endometritis is a puzzling disease that often associates with severe pelvic pain. In this study, we aimed to detect whether apigenin had protective effect against LPS-induced endometritis, if so, the underlying mechanism was further investigated. Apigenin was administrated 1 h before LPS treatment. The levels of inflammatory cytokines were measured by ELISA. The expression of NF-κB and Nrf2 were detected by Western blot analysis. The results showed that LPS treatment induced severe histological alteration of uterus and this change was attenuated by the treatment of apigenin. Apigenin significantly attenuated LPS-induced MPO activity, MDA content, and inflammatory cytokines TNF-α and IL-1ß production. LPS-induced NF-κB activation was suppressed by apigenin. Furthermore, apigenin elevated the expression of Nrf2 and HO-1 in uterine tissues. In conclusion, the present study demonstrated that apigenin protected against LPS-induced endometritis through activation of Nrf2 signaling pathway and inhibition of NF-κB signaling pathway.

Lysocardiolipin acyltransferase regulates TGF-ß mediated lung fibroblast differentiation.

Lysocardiolipin acyltransferase (LYCAT), a cardiolipin remodeling enzyme, plays a key role in mitochondrial function and vascular development. We previously reported that reduced LYCAT mRNA levels in peripheral blood mononuclear cells correlated with poor pulmonary function outcomes and decreased survival in IPF patients. Further LYCAT overexpression reduced lung fibrosis, and LYCAT knockdown accentuated experimental pulmonary fibrosis. NADPH Oxidase 4 (NOX4) expression and oxidative stress are known to contribute to lung fibroblast differentiation and progression of fibrosis. In this study, we investigated the role of LYCAT in TGF-ß mediated differentiation of human lung fibroblasts to myofibroblasts, and whether this occurred through mitochondrial superoxide and NOX4 mediated hydrogen peroxide (H2O2) generation. Our data indicated that LYCAT expression was up-regulated in primary lung fibroblasts isolated from IPF patients and bleomycin-challenged mice, compared to controls. In vitro, siRNA-mediated SMAD3 depletion inhibited TGF-ß stimulated LYCAT expression in human lung fibroblasts. ChIP immunoprecipitation assay revealed TGF-ß stimulated SMAD2/3 binding to the endogenous LYCAT promoter, and mutation of the SMAD2/3 binding sites (-179/-183 and -540/-544) reduced TGF-ß-stimulated LYCAT promoter activity. Overexpression of LYCAT attenuated TGF-ß-induced mitochondrial and intracellular oxidative stress, NOX4 expression and differentiation of human lung fibroblasts. Further, pretreatment with Mito-TEMPO, a mitochondrial superoxide scavenger, blocked TGF-ß-induced mitochondrial superoxide, NOX4 expression and differentiation of human lung fibroblasts. Treatment of human lung fibroblast with NOX1/NOX4 inhibitor, GKT137831, also attenuated TGF-ß induced fibroblast differentiation and mitochondrial oxidative stress. Collectively, these results suggest that LYCAT is a negative regulator of TGF-ß-induced lung fibroblast differentiation by modulation of mitochondrial superoxide and NOX4 dependent H2O2 generation, and this may serve as a potential therapeutic target for human lung fibrosis.

Fish intake and ovarian cancer risk: a meta-analysis of 15 case-control and cohort studies.

BACKGROUND: Previous epidemiological studies have shown that fish consumption may modify the risk of ovarian cancer. However, these studies yielded controversial results. The present meta-analysis was undertaken to evaluate the relationship between fish intake and ovarian cancer risk. METHODS: A literature search was carried out using Pubmed, Embase, and Cochrane Library Central database for all relevant studies up to August 2013. We pooled the relative risks (RR) from individual studies using fixed-effect or random-effect model, and carried out heterogeneity and publication bias analyses. RESULTS: A total of 15 (ten case-control, and five cohort) studies were included in the present meta-analysis, representing data for 889,033 female subjects and 6,087 ovarian cancer cases. We found that total fish intake was not significantly associated with the risk of ovarian cancer among cohort studies (RR = 1.04 95% CI [0.89, 1.22]) as well as case-control studies (RR = 0.90, 95% CI [0.73,1.12]). There was no evidence of publication bias as suggested by Begg's test (P = 0.55) and Egger's test(P = 0.29). CONCLUSIONS: The present meta-analysis showed that total fish consumption was not significantly associated with the risk of ovarian cancer. Further analysis on different fish species and food preparation methods should be conducted in future studies.

TPX2 regulates tumor growth in human cervical carcinoma cells.

The targeting protein for the Xenopus kinesin-like protein 2 (TPX2), a microtubule-associated protein, has been utilized as a tool to evaluate, more precisely, the proliferative behavior of tumor cells. The abnormal expression of TPX2 in a variety of malignant tumor types has been reported, however less is known about its role in cervical cancer. In the present study, the association between TPX2 expression and the biological behavior of cervical cancer, was investigated. Immunohistochemistry and RT-PCR were used to detect the expression of TPX2 in cervical cancer tissues. The inhibitory effect of TPX2-siRNA on the growth of SiHa human cervical carcinoma cells was studied in vitro. TPX2 expression was identified as significantly higher in cervical carcinoma compared with the control, normal cervical tissues. TPX2 siRNA transfected into SiHa cells induced apoptosis and inhibited cell proliferation and invasion. Similar results were obtained by in vivo transplantation, as TPX2 siRNA transfection significantly reduced tumor growth of the xenograft in nude mice. The results demonstrated that TPX2 is important in the regulation of tumor growth in cervical cancer and therefore may be a potential therapeutic target as a novel treatment strategy.

Human papillomavirus oncoproteins and apoptosis (Review).

The aim of this study was to review the literature and identify the association between human papillomavirus (HPV) oncoproteins and apoptosis. HPV-associated apoptosis may be primarily blocked by a number of oncoproteins, including E5, E6 and E7. E5 protein protects cells from tumor necrosis factor-associated apoptosis; the oncoprotein E6 predominantly inhibits apoptosis through the p53 pathway; and oncoprotein E7 is involved in apoptosis activation and inhibition. In addition, HPV oncoproteins are involved in activating or repressing the transcription of E6/E7. In conclusion, HPV oncoproteins, including E5, E6 and E7 protein, may interfere with apoptosis via certain regulatory principles.

A core cross-linked polymeric micellar platium(IV) prodrug with enhanced anticancer efficiency.

A core cross-linked polymeric micellar cisplatin(IV) conjugate prodrug is prepared by attaching the cisplatin(IV) to mPEG-b-PLL biodegradable copolymers to form micellar nanoparticles that can disintegrate to release the active anticancer agent cisplatin(II) in a mild reducing environment. Moreover, in vitro studies show that this cisplatin(IV) conjugate prodrug displays enhanced cytotoxicity against HepG2 cancer cells compared with cisplatin(II). Further studies demonstrate that the high cellular uptake and platinum-DNA adduct of this cisplatin(IV) conjugate prodrug can induce more cancer-cell apoptosis than cisplatin(II), which is responsible for its enhanced anticancer activity.