Association between ACE1 and missed abortion: ACE1 promotes H2O2-induced trophoblast cell injury in vitro†.

The aim of this study was to evaluate the role of angiotensin-converting enzyme 1 (ACE1) in H2O2-induced trophoblast cell injury and the potential molecular mechanisms. Oxidative stress was modeled by exposing HTR-8/SVneo cells to 200 µM H2O2. Western blot and real-time quantitative PCR methods were used to detect protein and mRNA expression level of ACE1 in chorionic villus tissue and trophoblast HTR-8/SVneo cell. Inhibition of ACE1 expression was achieved by transfection with small interfering RNA. Then flow cytometry, Cell Counting Kit-8, and Transwell assay was used to assess apoptosis, viability, and migration ability of the cells. Reactive oxygen species (ROS) were detected by fluorescent probes, and malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) activities were determined by corresponding detection kits. Angiotensin-converting enzyme 1 expression was upregulated in chorionic villus tissue of patients with missed abortion (MA) compared with individuals with normal early pregnancy abortion. H2O2 induced elevated ACE1 expression in HTR-8/SVneo cells, promoted apoptosis, and inhibited cell viability and migration. Knockdown of ACE1 expression inhibited H2O2-induced effects to enhance cell viability and migration and suppress apoptosis. Additionally, H2O2 stimulation caused increased levels of ROS and MDA and decreased SOD and GSH activity in the cells, whereas knockdown of ACE1 expression led to opposite changes of these oxidative stress indicators. Moreover, knockdown of ACE1 attenuated the inhibitory effect of H2O2 on the Nrf2/HO-1 pathway. Angiotensin-converting enzyme 1 was associated with MA, and it promoted H2O2-induced injury of trophoblast cells through inhibiting the Nrf2 pathway. Therefore, ACE1 may serve as a potential therapeutic target for MA.

Oncogenic Roles of Laminin Subunit Gamma-2 in Intrahepatic Cholangiocarcinoma via Promoting EGFR Translation.

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal biliary epithelial cancer in the liver. Here, Laminin subunit gamma-2 (LAMC2) with important oncogenic roles in iCCA is discovered. In a total of 231 cholangiocarcinoma patients (82% of iCCA patients) across four independent cohorts, LAMC2 is significantly more abundant in iCCA tumor tissue compared to normal bile duct and non-tumor liver. Among 26.3% of iCCA patients, LAMC2 gene is amplified, contributing to its over-expression. Functionally, silencing LAMC2 significantly blocks tumor formation in orthotopic iCCA mouse models. Mechanistically, it promotes EGFR protein translation via interacting with nascent unglycosylated EGFR in the endoplasmic reticulum (ER), resulting in activated EGFR signaling. LAMC2-mediated EGFR translation also depends on its interaction with the ER chaperone BiP via their C-terminus. Together LAMC2 and BiP generate a binding "pocket" of nascent EGFR and facilitate EGFR translation. Consistently, LAMC2-high iCCA patients have poor prognosis in two iCCA cohorts. LAMC2-high iCCA cells are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs) treatment both in vitro and in vivo. Together, these data demonstrate LAMC2 as an oncogenic player in iCCA by promoting EGFR translation and an indicator to identify iCCA patients who may benefit from available EGFR-targeted TKIs therapies.

One-Step Fabrication of Recyclable Konjac Glucomannan-Based Magnetic Nanoparticles for Highly Efficient Cr(VI) Adsorption.

Recently, the natural polymer polysaccharide konjac glucomannan (KGM) has received attention as a promising adsorbent in water treatment due to its low toxicity, cost-effectiveness and biocompatibility. However, the high-level water absorbency of KGM makes it difficult to recover in water treatment. In this study, by combining KGM with magnetic nanoparticles, KGM-based magnetic nanoparticles (KGM-Fe3O4 NPs) with excellent adsorption properties and recyclability for heavy metals were prepared using an one-step precipitation method. The as-prepared KGM-Fe3O4 NPs have a spherical morphology of superparamagnetism with a small particle size (ca. 7.0 nm) and a large specific surface area (160.1 m2·g-1). Taking Cr(VI) as the target heavy metal ion, the above nanoparticles have a high adsorption capacity and fast adsorption rate for Cr(VI). The pseudo-second order kinetic model is more suitable to describe the adsorption process of Cr(VI) by KGM-Fe3O4 NPs, and the maximum adsorption capacity of Cr(VI) onto KGM-Fe3O4 NPs was calculated to be 41.67 mg·g-1 using the Langmuir isotherm model. In addition, KGM-Fe3O4 NPs with adsorbed heavy metal ions can be quickly recovered from a solution, regenerated, and reused in the next cycle. KGM-based Fe3O4 nanoparticles are promising adsorbents that show significant reusability for the removal of metal ions in water and wastewater treatment.

Blocking hepatocarcinogenesis by a cytochrome P450 family member with female-preferential expression.

OBJECTS: The incidence of hepatocellular carcinoma (HCC) shows an obvious male dominance in rodents and humans. We aimed to identify the key autosomal liver-specific sex-related genes and investigate their roles in hepatocarcinogenesis. DESIGN: Two HCC cohorts (n=551) with available transcriptome and metabolome data were used. Class comparisons of omics data and ingenuity pathway analysis were performed to explore sex-related molecules and their associated functions. Functional assays were employed to investigate roles of the key candidates, including cellular assays, molecular assays and multiple orthotopic HCC mouse models. RESULTS: A global comparison of multiple omics data revealed 861 sex-related molecules in non-tumour liver tissues between female and male HCC patients, which denoted a significant suppression of cancer-related diseases and functions in female liver than male. A member of cytochrome P450 family, CYP39A1, was one of the top liver-specific candidates with significantly higher levels in female vs male liver. In HCC tumours, CYP39A1 expression was dramatically reduced in over 90% HCC patients. Exogenous CYP39A1 significantly blocked tumour formation in both female and male mice and partially reduced the sex disparity of hepatocarcinogenesis. The HCC suppressor role of CYP39A1 did not rely on its known P450 enzyme activity but its C-terminal region, by which CYP39A1 impeded the transcriptional activation activity of c-Myc, leading to a significant inhibition of hepatocarcinogenesis. CONCLUSIONS: The liver-specific CYP39A1 with female-preferential expression was a strong suppressor of HCC development. Strategies to up-regulate CYP39A1 might be promising methods for HCC treatment in both women and men in future.

MiR-125b Loss Activated HIF1α/pAKT Loop, Leading to Transarterial Chemoembolization Resistance in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Transarterial chemoembolization (TACE) is a standard locoregional therapy for patients with hepatocellular carcinoma (HCC) patients with a variable overall response in efficacy. We aimed to identify key molecular signatures and related pathways leading to HCC resistance to TACE, with the hope of developing effective approaches in preselecting patients with survival benefit from TACE. APPROACH AND RESULTS: Four independent HCC cohorts with 680 patients were used. MicroRNA (miRNA) transcriptome analysis in patients with HCC revealed a 41-miRNA signature related to HCC recurrence after adjuvant TACE, and miR-125b was the top reduced miRNA in patients with HCC recurrence. Consistently, patients with HCC with low miR-125b expression in tumor had significantly shorter time to recurrence following adjuvant TACE in two independent cohorts. Loss of miR-125b in HCC noticeably activated the hypoxia inducible factor 1 alpha subunit (HIF1α)/pAKT loop in vitro and in vivo. miR-125b directly attenuated HIF1α translation through binding to HIF1A internal ribosome entry site region and targeting YB-1, and blocked an autocrine HIF1α/platelet-derived growth factor ß (PDGFß)/pAKT/HIF1α loop of HIF1α translation by targeting the PDGFß receptor. The miR-125b-loss/HIF1α axis induced the expression of CD24 and erythropoietin (EPO) and enriched a TACE-resistant CD24-positive cancer stem cell population. Consistently, patients with high CD24 or EPO in HCC had poor prognosis following adjuvant TACE therapy. Additionally, in patients with HCC having TACE as their first-line therapy, high EPO in blood before TACE was also noticeably related to poor response to TACE. CONCLUSIONS: MiR-125b loss activated the HIF1α/pAKT loop, contributing to HCC resistance to TACE and the key nodes in this axis hold the potential in assisting patients with HCC to choose TACE therapy.

Genetic diversity and evolutionary features of type VI secretion systems in Salmonella.

AIM: Type VI secretion systems (T6SS) play key roles in bacterial pathogenesis, but their evolutionary features remain largely unclear. In this study, we conducted systematic comparisons among the documented T6SSs in Salmonella and determined their structural diversity, phylogenetic distribution and lineage-specific properties. MATERIALS & METHODS: We screened 295 Salmonella genomes for 13 T6SS core components by hidden Markov models and identified 363 T6SS clusters covering types i1, i2, i3 and i4a. RESULTS: Type i3 and i4a T6SSs were restricted to Salmonella enterica subspecies enterica and Salmonella bongori, respectively. whereas type i2 T6SSs were conserved between S. enterica subspecies, arizonae and diarizonae. S. enterica subspecies salamae, indica and houtenae harbored only type i1 T6SSs, which had wide distribution and high sequence diversity. CONCLUSION: The diverse Salmonella T6SSs have undergone purifying selection pressures during the bacterial evolution and may be involved in host adaptation.

[Study on relationship between tongue picture and cell apoptosis in patients with chronic gastritis].

OBJECTIVE: To study the characteristics of cell apoptosis in patients of chronic gastritis with different tongue pictures and its mechanism of formation. METHODS: The tongue picture, apoptosis index (AI) of lingual epithelial cells, apoptosis related gene proteins, such as p53, Bcl-2 and Fas in 109 patients of chronic superficial gastritis were observed. RESULTS: AI was different in patients with different tongue proper and tongue coating, those with pale white tongue and white thick coating had the maximum value of AI. (2) The p53, Bcl-2 and Fas expression positive rates in patients with different tongue pictures had corresponding changes, which were related not only with color of tongue, but also with color and thickness of tongue coating. CONCLUSION: The formation of tongue picture is closely related with cell apoptosis, p53, Bcl-2 and Fas take part in the regulation of cell apoptosis, which constitute together the cytologic basis of tongue picture in the disease.