SOX4 regulates proliferation and apoptosis of human ovarian granulosa-like tumor cell line KGN through the Hippo pathway.

The proliferation and apoptosis of ovarian granulosa cells are important for folliculogenesis. As a transcription factor, SRY-box transcription factor 4 (SOX4) has important roles in regulating cellular proliferation and apoptosis. Nonetheless, the regulatory mechanisms of SOX4 on proliferation and apoptosis of granulosa cells remain elusive. Therefore, a stably overexpressed SOX4 ovarian granulosa cell line KGN was generated by lentivirus encapsulation. We observed that overexpression of SOX4 inhibits apoptosis, promotes proliferation and migration of KGN cells. Comparative analysis of the transcriptome revealed 868 upregulated and 696 downregulated DEGs in LV-SOX4 in comparison with LV-CON KGN cell lines. Afterward, further assessments were performed to explore the possible functions about these DEGs. The data showed their involvement in many biological processes, particularly the Hippo signaling pathway. Moreover, the expression levels of YAP1, WWTR1, WTIP, DLG3, CCN2, and AMOT, which were associated with the Hippo signaling pathway, were further validated by qRT-PCR. In addition, the protein expression levels of YAP1 were markedly elevated, while p-YAP1 were notably reduced after overexpression of SOX4 in KGN cells. Thus, these results suggested that SOX4 regulates apoptosis, proliferation and migration of KGN cells, at least partly, through activation of the Hippo signaling pathway, which might be implicated in mammalian follicle development.

Paternal lipopolysaccharide exposure induced intrauterine growth restriction via the inactivation of placental MEST/PI3K/AKT pathway in mice.

Maternal lipopolysaccharide (LPS) exposure during pregnancy has been related to IUGR. Here, we explored whether paternal LPS exposure before mating impaired fetal development. All male mice except controls were intraperitoneally injected with LPS every other day for a total of five injections. The next day after the last LPS, male mice were mated with untreated female mice. Interestingly, fetal weight and crown-rump length were reduced, while the incidence of IUGR was increased in paternal LPS exposure group. Additionally, paternal LPS exposure leaded to poor placental development through causing cell proliferation inhibition and apoptosis. Additional experiment demonstrated that the inactivation of placental PI3K/AKT pathway might be involved in paternal LPS-induced cell proliferation inhibition and apoptosis of trophoblast cells. Furthermore, the mRNA and protein levels of mesoderm specific transcript (MEST), a maternally imprinted gene with paternal expression, were significantly decreased in mouse placentas from paternal LPS exposure. Further analysis showed that paternal LPS exposure caused the inactivation of placental PI3K/AKT pathway and then cell proliferation inhibition and apoptosis might be via down-regulating placental MEST. Overall, our results provide evidence that paternal LPS exposure causes poor placental development and subsequently IUGR may be via down-regulating MEST/PI3K/AKT pathway, and then inducing cell proliferation inhibition and apoptosis in placentas.

Efficient dose-volume histogram-based pretreatment patient-specific quality assurance methodology with combined deep learning and machine learning models for volumetric modulated arc radiotherapy.

BACKGROUND: Weak correlation between gamma passing rates and dose differences in target volumes and organs at risk (OARs) has been reported in several studies. Evaluation on the differences between planned dose-volume histogram (DVH) and reconstructed DVH from measurement was adopted and incorporated into patient-specific quality assurance (PSQA). However, it is difficult to develop a methodology allowing the evaluation of errors on DVHs accurately and quickly. PURPOSE: To develop a DVH-based pretreatment PSQA for volumetric modulated arc therapy (VMAT) with combined deep learning (DL) and machine learning models to overcome the limitation of conventional gamma index (GI) and improve the efficiency of DVH-based PSQA. METHODS: A DL model with a three-dimensional squeeze-and-excitation residual blocks incorporated into a modified U-net was developed to predict the measured PSQA DVHs of 208 head-and-neck (H&N) cancer patients underwent VMAT between 2018 and 2021 from two hospitals, in which 162 cases was randomly selected for training, 18 for validation, and 28 for testing. After evaluating the differences between treatment planning system (TPS) and PSQA DVHs predicted by DL model with multiple metrics, a pass or fail (PoF) classification model was developed using XGBoost algorithm. Evaluation of domain experts on dose errors between TPS and reconstructed PSQA DVHs was taken as ground truth for PoF classification model training. RESULTS: The prediction model was able to achieve a good agreement between predicted, measured, and TPS doses. Quantitative evaluation demonstrated no significant difference between predicted PSQA dose and measured dose for target and OARs, except for Dmean of PTV6900 (p = 0.001), D50 of PTV6000 (p = 0.014), D2 of PTV5400 (p = 0.009), D50 of left parotid (p = 0.015), and Dmax of left inner ear (p = 0.007). The XGBoost model achieved an area under curves, accuracy, sensitivity, and specificity of 0.89 versus 0.88, 0.89 versus 0.86, 0. 71 versus 0.71, and 0.95 versus 0.91 with measured and predicted PSQA doses, respectively. The agreement between domain experts and the classification model was 86% for 28 test cases. CONCLUSIONS: The successful prediction of PSQA doses and classification of PoF for H&N VMAT PSQA indicating that this DVH-based PSQA method is promising to overcome the limitations of GI and to improve the efficiency and accuracy of VMAT delivery.

An atlas-guided automatic planning approach for rectal cancer intensity-modulated radiotherapy.

We try to develop an atlas-guided automatic planning (AGAP) approach and evaluate its feasibility and performance in rectal cancer intensity-modulated radiotherapy. The developed AGAP approach consisted of four independent modules: patient atlas, similar patient retrieval, beam morphing (BM), and plan fine-tuning (PFT) modules. The atlas was setup using anatomy and plan data from Pinnacle auto-planning (P-auto) plans. Given a new patient, the retrieval function searched the top similar patient by a generic Fourier descriptor algorithm and retrieved its plan information. The BM function generated an initial plan for the new patient by morphing the beam aperture from the top similar patient plan. The beam aperture and calculated dose of the initial plan were used to guide the new plan optimization in the PFT function. The AGAP approach was tested on 96 patients by the leave-one-out validation and plan quality was compared with the P-auto plans. The AGAP and P-auto plans had no statistical difference for target coverage and dose homogeneity in terms ofV100%(p = 0.76) and homogeneity index (p = 0.073), respectively. The CI index showed they had a statistically significant difference. But the ΔCI was both 0.02 compared to the perfect CI index of 1. The AGAP approach reduced the bladder mean dose by 152.1 cGy (p < 0.05) andV50by 0.9% (p < 0.05), and slightly increased the left and right femoral head mean dose by 70.1 cGy (p < 0.05) and 69.7 cGy (p < 0.05), respectively. This work developed an efficient and automatic approach that could fully automate the IMRT planning process in rectal cancer radiotherapy. It reduced the plan quality dependence on the planner experience and maintained the comparable plan quality with P-auto plans.

Low Vitamin D Status Is Associated with Inflammation in Patients with Chronic Obstructive Pulmonary Disease.

Vitamin D deficiency is associated with increased risks of chronic obstructive pulmonary disease (COPD). Nevertheless, the mechanisms remain unknown. This study analyzed the correlations between vitamin D levels and inflammation in COPD patients. One hundred and one patients with COPD and 202 control subjects were enrolled. Serum 25(OH)D level and inflammatory cytokines were detected. Serum 25(OH)D was decreased and inflammatory cytokines were increased in COPD patients. According to forced expiratory volume in 1 s, COPD patients were divided into three grades. Furthermore, serum 25(OH)D was gradually decreased in COPD patients ranging from grade 1-2 to 4. Serum 25(OH)D was inversely associated with inflammatory cytokines in COPD patients. Further analysis found that NF-κB and AP-1 signaling were activated in COPD patients. Besides, inflammatory signaling was gradually increased in parallel with the severity of COPD. By contrast, pulmonary nuclear vitamin D receptor was decreased in COPD patients. In vitro experiments showed that 1,25(OH)2D3 inhibited LPS-activated inflammatory signaling in A549 cells (human lung adenocarcinoma cell). Mechanically, 1,25(OH)2D3 reinforced physical interactions between vitamin D receptor with NF-κB p65 and c-Jun. Our results indicate that vitamin D is inversely correlated with inflammatory signaling in COPD patients. Inflammation may be a vital mediator of COPD progress in patients with low vitamin D levels.

Magnesium sulfate prophylaxis attenuates the postpartum effects of preeclampsia by promoting M2 macrophage polarization.

Preeclampsia is a complex disorder that is characterized by new onset hypertension and proteinuria at or after 20 weeks of gestation. Preeclampsia is a leading cause of maternal and fetal morbidity and mortality. MgSO4 is commonly used to treat severe preeclampsia, but its mechanism of action is poorly understood, and investigations into the effects of MgSO4 during the postpartum period are lacking. In this study, timed-pregnant Sprague-Dawley rats received low-dose lipopolysaccharide (LPS) on gestational day 14 to induce preeclampsia. Maternal and fetal outcomes and the macrophage profile 1 week after delivery were explored. On postpartum day (PD) 7, the maternal systolic blood pressure and urinary protein level were significantly increased, the number of M1 macrophages was increased and the number of M2 macrophages was decreased in the maternal kidney and brain; the median duration of gestation, the number of live fetuses, and the fetal weight/placenta weight ratio were significantly decreased; and the percentage of growth-restricted pups and fetal mortality were significantly increased in preeclampsia rats compared to normal pregnant control rats. Prophylactic MgSO4 decreased blood pressure at PD7, improved pregnancy outcomes, and promoted the polarization of M2 macrophages in the kidney and of M2 microglia in the brain of preeclampsia rats. These findings confirm that the pathophysiology of preeclampsia involves the dysregulation of the inflammatory response and the activation of M1 macrophages in several target organs during pregnancy. MgSO4 prophylaxis attenuates the postpartum effects of preeclampsia by promoting M2 macrophage polarization in the maternal kidney and brain.

Environmental exposure to cadmium impairs fetal growth and placental angiogenesis via GCN-2-mediated mitochondrial stress.

Cadmium (Cd), a well-known environmental pollutant, can lead to placental insufficiency and fetal growth restriction. However, the underlying mechanism is unknown. The purpose of our study is to explore the effect of Cd on placental angiogenesis and its mechanism using in vitro and in vivo models. Results found that gestational Cd exposure obviously decreased placental weight and impaired placental vascular development in mice. Correspondingly, Cd exposure evidently downregulated the expression of VEGF-A protein (a key indicator of angiogenesis) and progesterone receptor (PR) in placental trophoblasts. Further experiment showed that lentivirus PR overexpression reversed Cd-caused the reduction of VEGF-A level in human placental trophoblasts. In addition, Cd significantly reduced progesterone level, down-regulated the expression of key progesterone synthase (StAR, CYP11A1), and activated mitochondrial stress response and GCN-2/p-eIF2α signaling in placental trophoblasts. Additional experiment showed that GCN-2 siRNA pretreatment markedly alleviated Cd-activated mitochondrial stress response, restored Cd-downregulated the expression of CYP11A1, reversed Cd-reduced the level of progesterone and VEGF-A in human placental trophoblasts. Finally, our case-control study confirmed that impaired placental angiogenesis and reduced progesterone level occurred in all-cause small for gestational age placenta. Taken together, environmental exposure to Cd impairs fetal growth and placental angiogenesis via GCN-2-mediated mitochondrial stress.

Gestational vitamin D deficiency impairs fetal lung development through suppressing type II pneumocyte differentiation.

Gestational vitamin D deficiency is associated with pulmonary diseases. This study aimed to investigate the effect of gestational vitamin D deficiency on fetal lung development in mice. Absolute and relative weights of fetal lungs were reduced in vitamin D deficient (VDD) group. Incrassate mesenchyme, measured by septal wall thickness, accompanied by lessened saccular space, was shown in VDD group. Numerous immature type II pneumocytes, as determined by PAS staining, were observed in VDD group. Moreover, increased Ki67-positive cells, a marker of cell proliferation, was detected in VDD group. The additional experiments showed that Sftpa, Sftpb, Sftpc and Sftpd, four surfactant genes, were downregulated and pro-surfactant protein B was reduced in VDD group. FoxA1, FoxA2 and TTF-1, three transcription factors that regulate surfactant genes, and VEGF, a key regulator for pulmonary maturation, were downregulated in VDD group. These results suggest that gestational vitamin D deficiency impairs fetal lung development partially through suppressing type II pneumocyte differentiation.

Association among placental 11ß-HSD2, PPAR-γ, and NF-κB p65 in small-for-gestational-age infants: A nested case-control study.

PROBLEM: 11ß-Hydroxysteroid dehydrogenase 2 (11ß-HSD2) catalyzes active glucocorticoids into their inactive products, preventing the passage of glucocorticoids into the fetus from maternal circulation. Peroxisome proliferator-activated receptor (PPAR)γ is a member of the nuclear receptor superfamily that regulates the expression of placental 11ß-HSD2. Nuclear factor-kappa B (NF-κB) is a transcription factor that regulates inflammatory signaling. This study aimed to investigate the association among 11ß-HSD2, PPAR-γ, and NF-κB p65 in small-for-gestational-age (SGA) infants. METHOD OF STUDY: Forty-six SGA and 46 appropriate-for-gestational-age (AGA) infants were enrolled in this study. Both newborns and placentas were weighed. Placental 11ß-HSD2 levels were measured using Western blotting. Placental PPAR-γ and NF-κB p65 were detected by immunohistochemistry. Placental inflammatory cytokines were evaluated by real-time RT-PCR. RESULTS: 11ß-HSD2 levels were lower in SGA placentas than those in AGA placentas. Placental PPAR-γ-positive nuclei were less in SGA than those in AGA. By contrast, placental NF-κB p65-positive nuclei were more in SGA than those in AGA. The levels of CRP, TNF-α, IL-8, and IL-1ß, several inflammatory cytokines, were higher in SGA placentas. Correlation analysis showed that neonatal weight was positively associated with PPAR-γ and 11ß-HSD2 in SGA placentas. By contrast, neonatal weight was inversely correlated with NF-κB p65 in SGA placentas. 11ß-HSD2 was positively correlated with PPAR-γ in SGA placentas. CONCLUSIONS: Inflammation-associated downregulation of placental PPAR-γ and 11ß-HSD2 may be involved in SGA.

Maternal cadmium exposure during late pregnancy causes fetal growth restriction via inhibiting placental progesterone synthesis.

Cadmium (Cd) is a major environmental pollutant. Maternal Cd exposure throughout pregnancy caused fetal growth restriction (FGR). However, the pivotal time window of Cd-evoked FGR and its mechanism are unknown. Here, we will establish a murine model to explore the effects of maternal Cd exposure at different stages of gestation on fetal growth and placental progesterone biosynthesis. Pregnant mice were randomly divided into four groups. For Cd groups, mice were given with CdCl2 (150 mg/L) through drinking water at early (GD0-GD6), middle (GD7-GD12) and late (GD13-GD17) gestation, respectively. The controls received reverses osmosis (RO) water. Results showed that maternal cadmium exposure only in late gestation lowered fetal weight and length. Correspondingly, placental Cd level in late gestational Cd exposure is the highest among three different gestational stages. Although gestational Cd exposure had few adverse effects in the weight and diameter of mouse placenta, placental vascular development, as determined by H&E staining and cluster of differentiation-34 (CD-34) immunostaining, was impaired in mice exposed to Cd during late pregnancy. Additionally, late gestational exposure to cadmium markedly reduced progesterone level in maternal serum and placenta. In line, the expression of key progesterone synthetases, including steroidogenic acute regulatory protein (StAR) and 3ß-hydroxyl steroid dehydrogenase (3ß-HSD), was obviously downregulated in placenta from mice was exposed Cd during late pregnancy. These data suggest that maternal Cd exposure during late pregnancy, but not early and middle pregnancy, induces fetal growth restriction partially via inhibiting placental progesterone synthesis.

Obeticholic Acid Protects against Gestational Cholestasis-Induced Fetal Intrauterine Growth Restriction in Mice.

Gestational cholestasis is a common disease and is associated with adverse pregnancy outcomes. However, there are still no effective treatments. We investigated the effects of obeticholic acid (OCA) on fetal intrauterine growth restriction (IUGR) during 17α-ethynylestradiol- (E2-) induced gestational cholestasis in mice. All pregnant mice except controls were subcutaneously injected with E2 (0.625 mg/kg) daily from gestational day (GD) 13 to GD17. Some pregnant mice were orally administered with OCA (5 mg/kg) daily from GD12 to GD17. As expected, OCA activated placental, maternal, and fetal hepatic FXR signaling. Additionally, exposure with E2 during late pregnancy induced cholestasis, whereas OCA alleviated E2-induced cholestasis. Gestational cholestasis caused reduction of fetal weight and crown-rump length and elevated the incidence of IUGR. OCA decreased the incidence of IUGR during cholestasis. Interestingly, OCA attenuated reduction of blood sinusoid area in placental labyrinth layer and inhibited downregulation of placental sodium-coupled neutral amino acid transporter- (SNAT-) 2 during cholestasis. Additional experiment found that OCA attenuated glutathione depletion and lipid peroxidation in placenta and fetal liver and placental protein nitration during cholestasis. Moreover, OCA inhibited the upregulation of placental NADPH oxidase-4 and antioxidant genes during cholestasis. OCA activated antioxidant Nrf2 signaling during cholestasis. Overall, we demonstrated that OCA treatment protected against gestational cholestasis-induced placental dysfunction and IUGR through suppressing placental oxidative stress and maintaining bile acid homeostasis.

Vitamin D deficiency exacerbates bleomycin-induced pulmonary fibrosis partially through aggravating TGF-ß/Smad2/3-mediated epithelial-mesenchymal transition.

BACKGROUND: Our earlier report indicated that active vitamin D3 inhibited epithelial-mesenchymal transition (EMT) in bleomycin (BLM)-induced pulmonary fibrosis. The objective of this study was to further investigate whether vitamin D deficiency exacerbates BLM-induced pulmonary fibrosis. METHODS: This study consists of two independent experiments. Experiment 1, male mice were fed with vitamin D deficient (VDD) fodder. Experiment 2, Cyp27b1+/+, Cyp27b1+/- and Cyp27b1-/- mice were fed with standard diet. For pulmonary fibrosis, mice were intratracheally instilled with a single dose of BLM (1.5 mg/kg). Serum 25(OH) D level was measured. Pulmonary collagen deposition was assessed by Sirius red staining. EMT was measured and transforming growth factor-beta (TGF-ß)/Smad3 signaling was evaluated in the lungs of BLM-treated mice. RESULTS: The relative weight of lungs was elevated in BLM-treated mice. Col1α1 and Col1α2, two collagen protein genes, were upregulated, and collagen deposition, as determined by Sirius red staining, was observed in the lungs of BLM-treated mice. E-cadherin, an epithelial marker, was downregulated. By contrast, vimentin and α-SMA, two EMT markers, were upregulated in the lungs of BLM-treated mice. Pulmonary TGF-ß/Smad3 signaling was activated in BLM-induced lung fibrosis. Further analysis showed that feeding VDD diet, leading to vitamin D deficiency, aggravated elevation of BLM-induced relative lung weight. Moreover, feeding VDD diet aggravated BLM-induced TGF-ß/Smad3 activation and subsequent EMT in the lungs. In addition, feeding VDD diet exacerbated BLM-induced pulmonary fibrosis. Additional experiment showed that Cyp27b1 gene knockout, leading to active vitamin D3 deficiency, exacerbated BLM-induced pulmonary fibrosis. Moreover, Cyp27b1 gene knockout aggravated pulmonary TGF-ß/Smad2/3 activation and subsequent EMT in BLM-induced lung fibrosis. CONCLUSION: Vitamin D deficiency exacerbates BLM-induced pulmonary fibrosis partially through aggravating TGF-ß/Smad2/3-mediated EMT in the lungs.

Activation of autophagy inhibits cadmium-triggered apoptosis in human placental trophoblasts and mouse placenta.

Cadmium (Cd), a ubiquitous environmental pollutant, is known to impair placental development. However, the underlying mechanisms remain unclear. The present study used in vivo and in vitro models to investigate the effects of Cd on apoptosis and autophagy in placental trophoblasts and its mechanism. Pregnant mice were exposed to CdCl2 (4.5 mg/kg) on gestational day (GD) 9. Human JEG-3 cells were exposed to CdCl2 (0-40 µM) for different time points. Gestational Cd exposure obviously lowered the weight and diameter of mouse placentas. Number of TUNEL-positive cells was markedly elevated in Cd-administered mouse placentas and JEG-3 cells. Correspondingly, Cd significantly up-regulated cleaved caspase-3 protein level, a key indicator of apoptosis, in murine placentas and JEG-3 cells. Simultaneously, Cd also triggered autophagy, as determined by an elevation of LC3B-II and p62 protein, and accumulation of LC3-positive puncta, in placental trophoblasts. Chloroquine an autophagy inhibitor, obviously aggravated Cd-induced apoptosis in JEG-3 cells. By contrast, rapamycin, a specific autophagy inducer, significantly alleviated Cd-triggered apoptosis in JEG-3 cells. Mechanistically, autophagy inhibited Cd-induced apoptosis mainly via degrading caspase-9. Co-localizations of p62, a classical autophagic receptor, and caspase-9 were observed in Cd-stimulated human JEG-3 cells. Moreover, p62 siRNAs pretreatment markedly blocked the degradation of caspase 9 proteins via Cd-activated autophagy in JEG-3 cells. Collectively, our data suggest that activation of autophagy inhibits Cd-induced apoptosis via p62-mediated caspase-9 degradation in placental trophoblasts. These findings provide a new mechanistic insight into Cd-induced impairments of placental and fetal development.

The correlation between low vitamin D status and renal interleukin-6/STAT3 hyper-activation in patients with clear cell renal cell carcinoma.

Low vitamin D status has been associated with increased risks of renal cell carcinoma (RCC). This study aimed to analyze the link between low vitamin D status and interleukin (IL)-6/STAT3 hyper-activation in clear cell RCC (ccRCC) patients. Forty-three newly diagnosed ccRCC patients and 86 age- and sex-matched controls were recruited. The association between low vitamin D status and IL-6/STAT3 hyper-activation was analyzed. Proliferation makersand STAT3 signal were evaluated. As expected, serum IL-6 level was higher in ccRCC patients than in controls. Moreover, serum IL-6 level was reversely correlated with serum 25(OH)D in ccRCC patients but not in controls. In addition, STAT3 signaling was hyper-activated in cancerous tissue. CcRCC patients were divided into three groups according to serum 25(OH)D level: vitamin D sufficiency (VitD-S, ≥30 ng/ml), vitamin D insufficiency (VitD-I, ≥20 and <30 ng/ml) or vitamin D deficiency (VitD-D, <20 ng/ml). Serum IL-6 was higher in ccRCC patients with VitD-D than those with VitD-S/VitD-I. Cancerous pSTAT3 level was higher in ccRCC patients with VitD-D than those with VitD-S/VitD-I. The number of pSTAT3+ nuclei in cancerous tissue was more in ccRCC patients with VitD-D than those with VitD-S/VitD-I. The expressions of cancerous PCNA, cyclin D1 and Ki-67, three markers of proliferation, were higher in ccRCC patients with VitD-D than those with VitD-S/VitD-I. The in vitro experiments showed that active vitamin D3 inhibited LPS-induced STAT3 phosphorylation in ACHN cells. Our results provide evidence that low vitamin D status is correlated with hyper-activation of cancerous IL-6/STAT3 and proliferation in ccRCC patients.

Lipopolysaccharide Downregulates 11ß-Hydroxysteroid Dehydrogenase 2 Expression through Inhibiting Peroxisome Proliferator-Activated Receptor-γ in Placental Trophoblasts.

It is increasingly recognized that excessive glucocorticoids induce fetal intrauterine growth restriction (IUGR). Placental 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2), a glucocorticoid-catalyzing enzyme, prevents active glucocorticoids from maternal circulation into the fetus, thus protecting against IUGR. Previous studies demonstrated gestational LPS exposure caused fetal IUGR. The aim of the current study was to investigate the effects of LPS on 11ß-HSD2 in mice placentas and human placental trophoblasts. Pregnant ICR(CD-1) mice were i.p. injected with LPS (200 µg/kg) on gestational day 16. As expected, gestational LPS exposure downregulated 11ß-HSD2 in mice placentas. In vitro, LPS downregulated 11ß-HSD2 in human placental trophoblasts. Additional experiment showed that LPS, which activated NF-κB, suppressed rosiglitazone-induced activation of peroxisome proliferator-activated receptor-γ (PPARγ) in mice placentas and human placental trophoblasts. Moreover, NF-κB p65 knockdown and specific NF-κB inhibitor attenuated LPS-induced suppression of PPARγ nuclear translocation in human placental trophoblasts. In addition, NF-κB p65 knockdown attenuated LPS-induced downregulation of 11ß-HSD2 in human placental trophoblasts. Mechanically, LPS promoted physical interaction between NF-κB p65 and PPARγ in the cytoplasm and nucleus of placental trophoblasts. Finally, pretreatment with rosiglitazone, a PPARγ agonist, partially alleviated LPS-induced reduction of fetal weight and crown-rump length. Taken together, these results suggest that LPS downregulates 11ß-HSD2 through suppressing PPARγ in placental trophoblasts. Placental 11ß-HSD2 downregulation may contribute partially to LPS-induced fetal IUGR.

miRNA-10a promotes cancer cell proliferation in oral squamous cell carcinoma by upregulating GLUT1 and promoting glucose metabolism.

MicroRNA-10a (miRNA-10a) promotes lung cancer; however, to the best of our knowledge, its involvement in other cancer types is unknown. The present study aimed to investigate the role of miRNA-10a in oral cancer. Expression levels of miRNA-10a and glucose transporter 1 (GLUT1) in tumor tissues and adjacent healthy tissues obtained from patients with oral squamous cell carcinoma (OSCC) were detected by reverse transcription-quantitative polymerase chain reaction. Correlation analysis between the expression levels of miRNA-10a and GLUT1 was performed using Pearson's correlation coefficient. It was identified that miRNA-10a and GLUT1 were upregulated in tumor tissues compared with adjacent healthy tissues of patients with OSCC. Expression levels of miRNA-10a and GLUT1 were positively correlated in tumor tissues but not in adjacent healthy tissues. In addition, miRNA-10a overexpression promoted glucose uptake and upregulated GLUT1 in OSCC cells. Furthermore, GLUT1 overexpression promoted glucose uptake; however, no significant increase in the expression level of miRNA-10a in OSCC cells was detected. Overexpression of miRNA-10a and GLUT1 promoted OSCC cell proliferation, while GLUT1-knockdown inhibited OSCC cell proliferation. GLUT1-knockdown also attenuated the enhancing effect of miRNA-10a overexpression on cancer cell proliferation. Therefore, miRNA-10a may promote cancer cell proliferation in OSCC by upregulating GLUT1 and promoting glucose metabolism.

[Study on the Quick Daily Check for Medical Electron LINAC].

This study presents an electronic portal imaging devices (EPIDs) based on daily check tool for Linac that is usable for different cancer centers.Several images of open rectangle fields were acquired with EPID and the key items of daily Linac check were derived from the obtained images using an in-house developed automatic analysis software.The experiment results showed that each parameter calculated by this tool is as reliable as the corresponding result measured by the commercial quality assurance devices and its measuring efficiency is much higher.

Pretreatment with Cholecalciferol Alleviates Renal Cellular Stress Response during Ischemia/Reperfusion-Induced Acute Kidney Injury.

BACKGROUND: Cellular stress is involved in ischemia/reperfusion- (I/R-) induced acute kidney injury (AKI). This study is aimed at investigating the effects of pretreatment with cholecalciferol on renal oxidative stress and endoplasmic reticulum (ER) stress during I/R-induced AKI. METHODS: I/R-induced AKI was established by cross-clamping renal pedicles for 90 minutes and then reperfusion. In the Chol + I/R group, mice were orally administered with three doses of cholecalciferol (25 µg/kg) at 1, 24, and 48 h before ischemia. Renal cellular stress and kidney injury were measured at different time points after reperfusion. RESULTS: I/R-induced AKI was alleviated in mice pretreated with cholecalciferol. In addition, I/R-induced renal cell apoptosis, as determined by TUNEL, was suppressed by cholecalciferol. Additional experiment showed that I/R-induced upregulation of renal GRP78 and CHOP was inhibited by cholecalciferol. I/R-induced renal IRE1α and eIF2α phosphorylation was attenuated by cholecalciferol. Moreover, I/R-induced renal GSH depletion, lipid peroxidation, and protein nitration were blocked in mice pretreated with cholecalciferol. I/R-induced upregulation of renal NADPH oxidases, such as p47phox, gp91phox, and nox4, was inhibited by cholecalciferol. I/R-induced upregulation of heme oxygenase- (HO-) 1, gshpx and gshrd, was attenuated in mice pretreated with cholecalciferol. CONCLUSIONS: Pretreatment with cholecalciferol protects against I/R-induced AKI partially through suppressing renal cellular stress response.

Oral cholecalciferol supplementation alleviates lipopolysaccharide-induced preterm delivery partially through regulating placental steroid hormones and prostaglandins in mice.

Several epidemiological reports demonstrated that vitamin D deficiency elevated risk of preterm delivery. We investigate the effects of oral cholecalciferol (VD3) supplementation on lipopolysaccharide (LPS)-induced preterm delivery. Pregnant mice were randomly assigned to either oral VD3 (25 µg/kg) or corn oil once daily from gestational day (GD)13 to GD15, and were intraperitoneally injected with either LPS (200 µg/kg) or normal saline on GD15. As expected, LPS was effective in inducing preterm delivery and fetal death. LPS-induced preterm delivery and fetal death were alleviated in VD3-pretreated mice. LPS-induced down-regulation of genes for placental progesterone biosynthetic enzymes was blocked in VD3-pretreated mice. LPS-induced reduction of serum progesterone was correspondingly attenuated by VD3. Although oral VD3 had no effect on estradiol production, it attenuated LPS-induced up-regulation of placental ERß in mice. LPS-induced placental COX-2 up-regulation and serum PGF2α elevation were alleviated in VD3-pretreated mice. Additionally, LPS-evoked elevations of the placental Tnfα, Il1ß, Mcp1 and Mip2 mRNAs were attenuated by VD3. VD3 promoted placental vitamin D receptor nuclear translocation and simultaneously alleviated LPS-induced nuclear translocation of NF-κB p65 and p50 subunits. These results provide evidence that oral VD3 supplementation alleviates LPS-induced preterm delivery and fetal demise partially through regulating placental steroid hormones and prostaglandins.

Obeticholic acid alleviate lipopolysaccharide-induced acute lung injury via its anti-inflammatory effects in mice.

Acute lung injury (ALI) is a common disease that may result in acute respiratory failure and death. However, there are still no effective treatments for ALI. Several studies have shown that farnesoid X receptor (FXR) has an anti-inflammatory effect. We investigated the effects of obeticholic acid (OCA), an agonist of FXR, on Lipopolysaccharide (LPS)-induced ALI in mice. Sixty male mice were randomly divided into six groups, and orally administered with or without OCA once daily for 3 consecutive days before LPS (1.0 mg/kg). Animals were sacrificed at 0 h, 2 h or 6 h after LPS. As expected, OCA enhanced pulmonary FXR activity. OCA prevented LPS-induced ALI. Additional experiment showed that OCA alleviated LPS-induced up-regulation of pulmonary pro-inflammatory and chemokine genes. Moreover, OCA also repressed LPS-induced the release of TNF-α and KC in serum and bronchoalveolar lavage fluid. In contrast, OCA further up-regulated LPS-induced the expression of Il-10, an anti-inflammatory cytokine. Further study showed that OCA inhibited LPS-evoked NF-κB signaling in the lungs. OCA attenuated LPS-induced ERK1/2, JNK, p38 and Akt phosphorylation in the lungs. Overall, these results suggest that OCA prevent LPS-induced ALI may be through enhancing pulmonary FXR activity and then blockading several inflammatory signaling pathways.