Pgrmc1 is a non-canonical progesterone receptor related to the lethality of various types of cancer. PGRMC1 has been reported to exist in co-precipitated protein complexes with epidermal growth factor receptor (EGFR), which is considered a useful therapeutic target in hepatocellular carcinoma (HCC). Here, we investigated whether Pgrmc1 is involved in HCC progression. In clinical datasets, PGRMC1 transcription level was positively correlated with EGFR levels; importantly, PGRMC1 level was inversely correlated with the survival duration of HCC patients. In a diethylnitrosamine (DEN)-induced murine model of HCC, the global ablation of Pgrmc1 suppressed the development of HCC and prolonged the survival of HCC-bearing mice. We further found that increases in hepatocyte death and suppression of compensatory proliferation in the livers of DEN-injured Pgrmc1-null mice were concomitant with decreases in nuclear factor κB (NF-κB)-dependent production of interleukin-6 (IL-6). Indeed, silencing of Pgrmc1 in murine macrophages led to reductions in NF-κB activity and IL-6 production. We found that the anti-proinflammatory effect of Pgrmc1 loss was mediated by reductions in EGFR level and its effect was not observed after exposure of the EGFR inhibitor erlotinib. This study reveals a novel cooperative role of Pgrmc1 in supporting the EGFR-mediated development of hepatocellular carcinoma, implying that pharmacological suppression of Pgrmc1 may be a useful strategy in HCC treatment.
N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), a synthetic additive widely used in the rubber industry, and its oxidized product 6PPD-quinone (6PPDQ), have garnered widespread attention as an emerging hazardous chemicals owing to their potential detrimental effects on aquatic ecosystem and human health. The effects of 6PPD and 6PPDq on the female reproductive tract, especially embryo implantation, remain unknown and were investigated in this study. We used the spheroid attachment and outgrowth models of BeWo trophoblastic spheroids and Ishikawa cells as surrogates for the human blastocyst and endometrial epithelium, respectively. Treatment with the chemicals for up to 48 h decreased the viability of the cells in a dose- and cell line-dependent manner (20-100 μM 6PPD and 10-100 μM 6PPDQ for both the cell lines). At a noncytotoxic concentration, exposure of Ishikawa cells to 1 and 10 μM 6PPD reduced the attachment of BeWo spheroids and further inhibited their invasion and outgrowth on the endometrial epithelial monolayer. A similar result was observed in 1 μM 6PPDQ-exposed groups. Gene expression profiling of 6PPD- and 6PPDQ-exposed endometrial epithelial cells revealed that both 6PPD and 6PPDQ differentially regulated a panel of transcript markers toward overall downregulation of receptivity and invasion. The study provides the first proof of the adverse effects of 6PPD and 6PPDQ on human endometrial receptivity and trophoblast invasion during the window of implantation, warranting the need for further in vivo and clinical studies.
After maternal intake, nicotine crosses the placental barrier and causes severe embryonic disorders and fetal death. In this study, we investigated whether β -carotene has a beneficial effect against nicotine-induced teratogenesis in mouse embryos (embryonic day 8.5) cultured for 48 h in a whole embryo culture system. Embryos exposed to nicotine (1 mM) exhibited severe morphological anomalies and apoptotic cell death, as well as increased levels of TNF- α , IL-1 β , and caspase 3 mRNAs, and lipid peroxidation. The levels of cytoplasmic superoxide dismutase (SOD), mitochondrial manganese-dependent SOD, cytosolic glutathione peroxidase (GPx), phospholipid hydroperoxide GPx, hypoxia inducible factor 1 α , and Bcl-x L mRNAs decreased, and SOD activity was reduced compared to the control group. However, when β -carotene (1 × 10(-7) or 5 × 10(-7) μM) was present in cultures of embryos exposed to nicotine, these parameters improved significantly. These findings indicate that β -carotene effectively protects against nicotine-induced teratogenesis in mouse embryos through its antioxidative, antiapoptotic, and anti-inflammatory activities.
Abstract Background and Aim We aimed to assess the gene expression profiles of nonlesional small bowels in patients with Crohn's disease (CD) to identify its accompanying molecular alterations. Methods We performed RNA sequencing of the uninflamed small bowel tissues obtained from 70 patients with ileal CD and 9 patients with colon cancer (non‐CD controls) during bowel resection. Differentially expressed gene (DEG) analyses were performed using DESeq2. Gene set enrichment, correlation, and cell deconvolution analyses were applied to identify modules and functionally enriched transcriptional signatures of CD. Results A comparison of CD patients and non‐CD controls revealed that of the 372 DEGs, 49 protein‐coding genes and 5 long non‐coding RNAs overlapped with the inflammatory bowel disease susceptibility loci. The pathways related to immune and inflammatory reactions were upregulated in CD, while metabolic pathways were downregulated in CD. Compared with non‐CD controls, CD patients had significantly higher proportions of immune cells, including plasma cells ( P = 1.15 × 10 −4 ), and a lower proportion of epithelial cells ( P = 1.12 × 10 −4 ). Co‐upregulated genes (M14 module) and co‐downregulated genes (M9 module) were identified in CD patients. The M14 module was enriched in immune‐related genes and significantly associated with the responses to anti‐tumor necrosis factor (TNF) therapy. The core signature of the M14 module was comprised of six genes and was upregulated in nonresponders to anti‐TNF therapy of five independent cohorts ( n = 163), indicating acceptable discrimination ability (area under the receiver operating characteristic curve of 75–86%). Conclusions The differences in gene expression and cellular composition between CD patients and non‐CD controls imply significant molecular alterations, which are associated with the response to anti‐TNF treatment.
Radiation-induced lung injury (RILI) due to nuclear or radiological exposure remains difficult to treat because of insufficient clinical data. The goal of this study was to establish an appropriate and efficient minipig model and introduce a thoracic computed tomography (CT)-based method to measure the progression of RILI. Göttingen minipigs were allocated to control and irradiation groups. The most obvious changes in the CT images after irradiation were peribronchial opacification, interlobular septal thickening, and lung volume loss. Hounsfield units (HU) in the irradiation group reached a maximum level at 6 weeks and decreased thereafter, but remained higher than those of the control group. Both lung area and cardiac right lateral shift showed significant changes at 22 weeks post irradiation. The white blood cell (WBC) count, a marker of pneumonitis, increased and reached a maximum at 6 weeks in both peripheral blood and bronchial alveolar lavage fluid. Microscopic findings at 22 weeks post irradiation were characterized by widening of the interlobular septum, with dense fibrosis and an increase in the radiation dose-dependent fibrotic score. Our results also showed that WBC counts and microscopic findings were positively correlated with the three CT parameters. In conclusion, the minipig model can provide useful clinical data regarding RILI caused by the adverse effects of high-dose radiotherapy. Peribronchial opacification, interlobular septal thickening, and lung volume loss are three quantifiable CT parameters that can be used as a simple method for monitoring the progression of RILI.
Purpose . Radiation-induced lung fibrosis (RILF) is a serious late complication of radiotherapy. In vitro studies have demonstrated that pentoxifylline (PTX) has suppressing effects in extracellular matrix production in fibroblasts, while the antifibrotic action of PTX alone using clinical dose is yet unexplored. Materials and Methods . We used micro-computed tomography (micro-CT) and histopathological analysis to evaluate the antifibrotic effects of PTX in a rat model of RILF. Results . Micro-CT findings showed that lung density, volume loss, and mediastinal shift are significantly increased at 16 weeks after irradiation. Simultaneously, histological analysis demonstrated thickening of alveolar walls, destruction of alveolar structures, and excessive collagen deposition in the irradiated lung. PTX treatment effectively attenuated the fibrotic changes based on both micro-CT and histopathological analyses. Western analysis also revealed increased levels of plasminogen activator inhibitor- (PAI-) 1 and fibronectin (FN) and PTX treatment reduced expression of PAI-1 and FN by restoring protein kinase A (PKA) phosphorylation but not TGF- β /Smad in both irradiated lung tissues and epithelial cells. Conclusions . Our results demonstrate the antifibrotic effect of PTX on radiation-induced lung fibrosis and its effect on modulation of PKA and PAI-1 expression as possible antifibrotic mechanisms.
Nicotine, a major toxic component in tobacco smoke, leads to severe embryonic damages on organogenesis. We investigated if resveratrol can inhibit the nicotine–induced teratogenesis in the cultured mouse embryos (embryonic day 8.5) for 48 hours using a whole embryo culture system. The embryos exposed to nicotine (1 μM) revealed severe morphological anomalies, the increased levels of caspase-3 mRNA and lipid peroxidation, and further the lowered levels of mitochondrial manganese superoxide dismutase (SOD), cytosolic glutathione peroxidase (GPx), phospholipid hydroperoxide GPx, hypoxia-inducible factor 1α, and sirtuin mRNAs and SOD activity significantly compared to normal control group (p<0.05). However, whenre sveratrol(1×10‒5 μMor1 ×10‒4 μM) was added concurrently to the embryos exposed to nicotine, these all parameters were significantly improved (p<0.05).These findings indicate that resveratrol has a protective effect against nicotine-induced teratogenesis in mouse embryos throughout antioxidative and anti-apoptotic activities.
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