Molecular mechanisms of cadmium-induced cytotoxicity in human ovarian granulosa cells identified using integrated omics.

Epidemiological and clinical data have demonstrated that exposure to cadmium (Cd), a toxic heavy metal, is associated with an increased risk of female infertility. Granulosa cells, the main somatic cells comprising ovarian follicles, are one of the main targets of Cd in the ovaries. However, the mechanism by which Cd induces cytotoxicity in granulosa cells has not been fully elucidated. In this study, we exposed human ovarian granulosa cells (KGN cells) to Cd and conducted in vitro cell experiments and multi-omics (metabolomics and transcriptomics) methods to elucidate these mechanisms. Cd exposure was found to not only induce the apoptosis of the KGN cells but also further reduced mitochondrial function by decreasing mitochondrial membrane potential, ATP production, and respiratory chain complex activity as well as increasing mitochondrial reactive oxygen species (ROS) production. A total of 443 differentially expressed metabolites (160 upregulated and 283 downregulated) and 5200 differentially expressed genes (4634 upregulated and 566 downregulated) were observed in the Cd exposed-cells. The multi-omics data showed that Cd interfered with citric acid cycle (TCA cycle), amino acid (including alanine, glycine, serine, threonine, arginine, and proline) metabolism, and calcium signaling. These findings help to better elucidate the potential toxicity mechanisms of Cd on granulosa cells and the ovary.

Zinc finger and SCAN domain-containing protein 18 is a potential DNA methylation-modified tumor suppressor and biomarker in breast cancer.

Introduction: Zinc finger and SCAN domain-containing protein 18 (ZSCAN18) has been investigated as a putative biomarker of multiple human cancers. However, the expression profile, epigenetic modification, prognostic value, transcription regulation, and molecular mechanism of ZSCAN18 in breast cancer (BC) remain unknown. Methods: In the study, we present an integrated analysis of ZSCAN18 in BC based on public omics datasets with the use of multiple bioinformatics tools. Genes potentially regulated through restoration of ZSCAN18 expression in MDA-MB-231 cells were investigated to identify pathways associated with BC. Results: We observed that ZSCAN18 was downregulated in BC and mRNA expression was significantly correlated with clinicopathological parameters. Low expression of ZSCAN18 was found in the HER2-positive and TNBC subtypes. High expression of ZSCAN18 was associated with good prognosis. As compared to normal tissues, the extent of ZSCAN18 DNA methylation was greater with fewer genetic alterations in BC tissues. ZSCAN18 was identified as a transcription factor that might be involved in intracellular molecular and metabolic processes. Low ZSCAN18 expression was associated with the cell cycle and glycolysis signaling pathway. Overexpression of ZSCAN18 inhibited mRNA expression of genes associated with the Wnt/ß-catenin and glycolysis signaling pathways, including CTNNB1, BCL9, TSC1, and PFKP. ZSCAN18 expression was negatively correlated with infiltrating B cells and dendritic cells (DCs), as determined by the TIMER web server and reference to the TISIDB. ZSCAN18 DNA methylation was positively correlated with activated B cells, activated CD8+ and CD4+ T cells, macrophages, neutrophils, and activated DCs. Moreover, five ZSCAN18-related hub genes (KDM6B, KAT6A, KMT2D, KDM1A, and HSPBP1) were identified. ZSCAN18, ZNF396, and PGBD1 were identified as components of a physical complex. Conclusion: ZSCAN18 is a potential tumor suppressor in BC, as expression is modified by DNA methylation and associated with patient survival. In addition, ZSCAN18 plays important roles in transcription regulation, the glycolysis signaling pathway, and the tumor immune microenvironment.

Soluble fibrinogen-like protein 2 ameliorates acute rejection of liver transplantation in rat via inducing Kupffer cells M2 polarization.

Soluble fibrinogen-like protein 2 (sFGL2) could ameliorate acute rejection (AR) in rat cardiac transplantation. However, the role of sFGL2 in AR of liver transplantation has not been addressed. In this study, we found that FGL2 was upregulated in rat orthotropic liver transplantation (OLT) models of tolerance and positive correlation with the frequency of M2 Kupffer cells (KCs). Gain-of-function experiments in vitro showed that sFGL2 promoted the secretion of anti-inflammatory cytokines (IL-10, TGF-ß) and the expression of CD206, and inhibited the activities of STAT1 and NF-κB signaling pathway. Consistently, in vivo assays showed that adeno-associated virus-mediated FGL2 (AAV-FGL2) transfer to recipients could ameliorate AR of rat OLT and induce KCs M2 polarization in allografts. Notably, we found that the recipients receiving transferred KCs from AAV-FGL2-treated allograft showed alleviated AR. Taken together, we revealed that sFGL2 ameliorated AR by inducing KCs M2 polarization.

IL-34 Inhibits Acute Rejection of Rat Liver Transplantation by Inducing Kupffer Cell M2 Polarization.

BACKGROUND: Recent studies have demonstrated that IL-34 is implicated in the regulation of macrophage functions. However, the effect of IL-34 on Kupffer cells (KCs) in acute rejection (AR) of liver transplantation remains unclear. METHODS: IL-34 expression was detected in graft and serum from allotransplantation and syngeneic transplantation groups. The adeno-associated virus-expressing IL-34 was used to assess the effect of IL-34 on AR of rat liver transplantation. The effect of IL-34 on KC polarization was evaluated by in vitro and in vivo assays. Kupffer cells in donors were depleted by clodronate treatment before transplantation, and the nontreated KCs or lipopolysaccharide-treated KCs were transferred into recipients during liver transplantation. RESULTS: IL-34 expression levels in grafts and serum were decreased in the allotransplantation group compared with the syngeneic transplantation group. Adeno-associated virus-expressing IL-34 treatment induced KC M2 polarization in vivo and inhibited the AR of rat liver transplantation. Moreover, we found that IL-34 switched the phenotype of KCs from M1 to M2 by activating the PI3K/Akt pathway in vitro. In addition, the results of KC deletion and adaptive transfer experiments showed that the AR inhibition induced by IL-34 was M2 KC-dependent. CONCLUSIONS: IL-34 plays an important role in KC M2 polarization-dependent AR inhibition of rat liver transplantation.

Clinical Features and Therapeutic Options for Isolated Visceral Artery Dissection.

BACKGROUND: The diagnosis of isolated visceral artery dissection (IVAD) has become more common with the increasing use of computed tomography angiography (CTA). We examined the presentation, treatment, and outcomes of patients with IVAD treated at our institution. METHODS: The records of 72 patients treated for IVAD between January 2010 and August 2014 were analyzed retrospectively. All were treated with antiplatelet or anticoagulant drugs after admission and were continued on oral aspirin for at least 1 year. Four asymptomatic and 52 symptomatic patients were managed conservatively with blood pressure control, bowel rest, fluid supplementation, and nutritional support. Two patients underwent open surgery because of hematochezia and 16 underwent endovascular bare-metal stenting. RESULTS: Symptoms gradually resolved in those treated conservatively, and favorable arterial wall remodeling was observed in 16 patients. Twenty-one stents were implanted in 16 patients with superior mesenteric artery dissection; 3 patients required overlapping stents. During follow-up (range, 3-53 months), all patients were symptom-free, and there were no recurrences. Follow-up CTA of patients who underwent endovascular stenting demonstrated satisfactory stent and true lumen patency. CONCLUSIONS: IVAD is not uncommon. It occurs most frequently between the ages of 46 and 60 years and affects more men than women. A favorable outcome can be achieved in most of the patients with conservative management. Ischemic bowel necrosis is rare but requires open surgery. Endovascular bare-metal stenting is recommended when there is persistent abdominal pain, progression of the lesion, apparent stenosis of a true lumen compressed by a false lumen, or dilation of false lumen at a high risk of rupture.

Influence of Iliac Vein Stent Implantation on the Contralateral Iliac Vein.

OBJECTIVES: Stent implantation is frequently used to treat iliac vein occlusion. However, the recommended extension of the stent mesh into the inferior vena cava (IVC) may affect blood flow through the contralateral iliac vein. We analyzed the influence of iliac vein stent extension on contralateral iliac vein patency and neointima formation in a dog surgery model. METHODS: Bare stents were implanted into the left iliac veins of 12 beagles with the proximal end covering the opening of the contralateral iliac vein. Blood flow was measured by color Doppler 4, 8, and 12 weeks postoperation. At each measurement point, a subgroup was killed, and the stents and veins were removed for pathological examination. RESULTS: Stents were successfully implanted, and there was no immediate stent occlusion or iliac vein thrombus by color Doppler examinations. Contralateral blood flow was maintained with no obvious abnormalities for 12 weeks. Neointima formed and advanced toward the center of the stent, but small coverage of the contralateral iliac vein opening did not change significantly with time postoperation (9.33% ± 1.54% at 4 weeks, 10.65% ± 1.01% at 8 weeks, and 10.92% ± 1.30% at 12 weeks; P > .05). Scanning electron microscopy showed neointima covering the surface of stent wires at the opening of the contralateral iliac vein, which did increase with time: 63.58% ± 12.39% at 4 weeks, 97.13% ± 2.71% at 8 weeks (P < .001 vs 4 weeks), and 99.63% ± 0.60% after 12 weeks (P > .05 vs 8 weeks; P < .001 vs 4 weeks). The neointimal coverage rate of the meshes increased obviously with time. However, no neointima was found forming a mesh between stent wires. CONCLUSION: Although there was intimal hyperplasia on the rim of the bare stent in the IVC, expansion was limited and did not block the opening of the contralateral iliac vein. The stent had no obvious influence on blood backflow in the contralateral iliac vein.