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Browsing by Author "Liu, X."
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Item Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer(SpringerNature, 2016-12-15) Li, J.; Gu, D.; Lee, SS-Y.; Song, B.; Bandyopadhyay, S.; Chen, S.; Konieczny, SF.; Ratliff, TL.; Liu, X.; Xie, J.; Cheng, J-X.; Department of Pediatrics, IU School of MedicineCancer cells are known to execute reprogramed metabolism of glucose, amino acids and lipids. Here, we report a significant role of cholesterol metabolism in cancer metastasis. By using label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester in human pancreatic cancer specimens and cell lines, mediated by acyl-CoA cholesterol acyltransferase-1 (ACAT-1) enzyme. Expression of ACAT-1 showed a correlation with poor patient survival. Abrogation of cholesterol esterification, either by an ACAT-1 inhibitor or by shRNA knockdown, significantly suppressed tumor growth and metastasis in an orthotopic mouse model of pancreatic cancer. Mechanically, ACAT-1 inhibition increased intracellular free cholesterol level, which was associated with elevated endoplasmic reticulum stress and caused apoptosis. Collectively, our results demonstrate a new strategy for treating metastatic pancreatic cancer by inhibiting cholesterol esterification.Item Inhibition of APE1/Ref-1 redox activity rescues human retinal pigment epithelial cells from oxidative stress and reduces choroidal neovascularization(2014-02) Li, Y.; Liu, X.; Zhou, T.; Kelley, Mark R.; Edwards, P.; Gao, H.; Qiao, XiaoxiThe effectiveness of current treatment for age related macular degeneration (AMD) by targeting one molecule is limited due to its multifactorial nature and heterogeneous pathologies. Treatment strategy to target multiple signaling pathways or pathological components in AMD pathogenesis is under investigation for better clinical outcome. Inhibition of the redox function of apurinic endonuclease 1/redox factor-1 (APE1) was found to suppress endothelial angiogenesis and promote neuronal cell recovery, thereby may serve as a potential treatment for AMD. In the current study, we for the first time have found that a specific inhibitor of APE1 redox function by a small molecule compound E3330 regulates retinal pigment epithelium (RPEs) cell response to oxidative stress. E3330 significantly blocked sub-lethal doses of oxidized low density lipoprotein (oxLDL) induced proliferation decline and senescence advancement of RPEs. At the same time, E3330 remarkably decreased the accumulation of intracellular reactive oxygen species (ROS) and down-regulated the productions of monocyte chemoattractant protein-1 (MCP-1) and vascular endothelial growth factor (VEGF), as well as attenuated the level of nuclear factor-κB (NF-κB) p65 in RPEs. A panel of stress and toxicity responsive transcription factors that were significantly upregulated by oxLDL was restored by E3330, including Nrf2/Nrf1, p53, NF-κB, HIF1, CBF/NF-Y/YY1, and MTF-1. Further, a single intravitreal injection of E3330 effectively reduced the progression of laser-induced choroidal neovascularization (CNV) in mouse eyes. These data revealed that E3330 effectively rescued RPEs from oxidative stress induced senescence and dysfunctions in multiple aspects in vitro, and attenuated laser-induced damages to RPE–Bruch׳s membrane complex in vivo. Together with its previously established anti-angiogenic and neuroprotection benefits, E3330 is implicated for potential use for AMD treatment.Item Molecular Basis for Craniofacial Phenotypes Caused by Sclerostin Deletion(Sage, 2021) Chen, J.; Yuan, X.; Pilawski, I.; Liu, X.; Delgado-Calle, J.; Bellido, T.; Turkkahraman, H.; Helms, J.A.; Medicine, School of MedicineSome genetic disorders are associated with distinctive facial features, which can aid in diagnosis. While considerable advances have been made in identifying causal genes, relatively little progress has been made toward understanding how a particular genotype results in a characteristic craniofacial phenotype. An example is sclerosteosis/van Buchem disease, which is caused by mutations in the Wnt inhibitor sclerostin (SOST). Affected patients have a high bone mass coupled with a distinctive appearance where the mandible is enlarged and the maxilla is foreshortened. Here, mice carrying a null mutation in Sost were analyzed using quantitative micro-computed tomographic (µCT) imaging and histomorphometric analyses to determine the extent to which the size and shape of craniofacial skeleton were altered. Sost-/- mice exhibited a significant increase in appositional bone growth, which increased the height and width of the mandible and reduced the diameters of foramina. In vivo fluorochrome labeling, histology, and immunohistochemical analyses indicated that excessive bone deposition in the premaxillary suture mesenchyme curtailed overall growth, leading to midfacial hypoplasia. The amount of bone extracellular matrix produced by Sost-/- cells was significantly increased; as a consequence, osteoid seams were evident throughout the facial skeleton. Collectively, these analyses revealed a remarkable fidelity between human characteristics of sclerosteosis/van Buchem disease and the Sost-/- phenotype and provide clues into the conserved role for sclerostin signaling in modulating craniofacial morphology.Item The patterns and implications of diurnal variations in the d-excess of plant water, shallow soil water and air moisture(2014-10) Zhao, L.; Wang, Lixin; Liu, X.; Xiao, H.; Ruan, Y.; Zhou, M.Deuterium excess (d-excess) of air moisture is traditionally considered a conservative tracer of oceanic evaporation conditions. Recent studies challenge this view and emphasize the importance of vegetation activity in controlling the dynamics of air moisture d-excess. However, direct field observations supporting the role of vegetation in d-excess variations are not well documented. In this study, we quantified the d-excess of air moisture, shallow soil water (5 and 10 cm) and plant water (leaf, root and xylem) of multiple dominant species at hourly intervals during three extensive field campaigns at two climatically different locations within the Heihe River basin, northwestern China. The ecosystems at the two locations range from forest to desert. The results showed that with the increase in temperature (T) and the decrease in relative humidity (RH), the δD–δ18O regression lines of leaf water, xylem water and shallow soil water deviated gradually from their corresponding local meteoric water line. There were significant differences in d-excess values between different water pools at all the study sites. The most positive d-excess values were found in air moisture (9.3‰) and the most negative d-excess values were found in leaf water (−85.6‰). The d-excess values of air moisture (dmoisture) and leaf water (dleaf) during the sunny days, and shallow soil water (dsoil) during the first sunny day after a rain event, showed strong diurnal patterns. There were significantly positive relationships between dleaf and RH and negative relationships between dmoisture and RH. The correlations of dleaf and dmoisture with T were opposite to their relationships with RH. In addition, we found opposite diurnal variations for dleaf and dmoisture during the sunny days, and for dsoil and dmoisture during the first sunny day after the rain event. The steady-state Craig–Gordon model captured the diurnal variations in dleaf, with small discrepancies in the magnitude. Overall, this study provides a comprehensive and high-resolution data set of d-excess of air moisture, leaf, root, xylem and soil water. Our results provide direct evidence that dmoisture of the surface air at continental locations can be significantly altered by local processes, especially plant transpiration during sunny days. The influence of shallow soil water on dmoisture is generally much smaller compared with that of plant transpiration, but the influence could be large on a sunny day right after rainfall events.Item Soil methane and carbon dioxide fluxes from cropland and riparian buffers in different hydrogeomorphic settings(ACSESS, 2015) Jacinthe, Pierre-André; Vidon, P.; Fisher, K.; Liu, X.; Baker, M. E.; Department of Earth Sciences, School of ScienceRiparian buffers contribute to the mitigation of nutrient pollution in agricultural landscapes, but there is concern regarding their potential to be hot spots of greenhouse gas production. This study compared soil CO2 and CH4 fluxes in adjacent crop fields and riparian buffers (a flood-prone forest and a flood-protected grassland along an incised channel) and examined the impact of water table depth (WTD) and flood events on the variability of gas fluxes in riparian zones. Results showed significantly (P < 0.001) higher CO2 emission in riparian areas than in adjoining croplands (6.8 ± 0.6 vs. 3.6 ± 0.5 Mg CO2–C ha−1 yr−1; mean ± SE). Daily flux of CO2 and soil temperature were significantly related (P < 0.002), with Q10 values ranging between 1.75 and 2.53. Significant relationships (P < 0.05) were found between CH4 daily flux and WTD. Flood events resulted in enhanced CH4 emission (up to +44.5 mg CH4–C m−2 d−1 in a swale) under warm soil conditions (>22°C), but the effect of flooding was less pronounced in early spring (emission <1.06 mg CH4–C m−2 d−1), probably due to low soil temperature. Although CH4 flux direction alternated at all sites, overall the croplands and the flood-affected riparian forest were CH4 sources, with annual emission averaging +0.04 ± 0.17 and +0.92 ± 1.6 kg CH4–C ha−1, respectively. In the riparian forest, a topographic depression (<8% of the total area) accounted for 78% of the annual CH4 emission, underscoring the significance of landscape heterogeneity on CH4 dynamics in riparian buffers. The nonflooded riparian grassland, however, was a net CH4 sink (−1.08 ± 0.22 kg CH4–C ha−1 yr−1), probably due to the presence of subsurface tile drains and a dredged/incised channel at that study site. Although these hydrological alterations may have contributed to improvement in the CH4 sink strength of the riparian grassland, this must be weighed against the water quality maintenance functions and other ecological services provided by riparian buffers.