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Hepatic hypoxia

Charles Cai, Taimur Ahmad, Gloria B Valencia, Jacob V Aranda, Jiliu Xu, Kay D Beharry
OBJECTIVES: Extremely low gestational age neonates with chronic lung disease requiring oxygen therapy frequently experience fluctuations in arterial oxygen saturation or intermittent hypoxia (IH). These infants are at risk for multi-organ developmental delay, reduced growth, and short stature. The growth hormone (GH)/insulin-like growth factor-I (IGF-1) system, an important hormonal regulator of lipid and carbohydrate metabolism, promotes neonatal growth and development. We tested the hypothesis that increasing episodes of IH delay neonatal growth by influencing the GH/IGF-I axis...
March 8, 2018: Growth Hormone & IGF Research
Jeong-Min Hong, Sun-Mee Lee
AIMS: Heme oxygenase-1 (HO-1), an endogenous cytoprotective enzyme, is reported that can be localized in mitochondria under stress, contributing to preserve mitochondrial function. Mitochondrial quality control (QC) is essential to cellular health and recovery linked with redox homeostasis. Recent studies reported that phosphoglycerate mutase family member (PGAM) 5, a mitochondria-resident phosphatase, plays critical role in mitochondrial homeostasis. Therefore, we aim to investigate cytoprotective mechanisms of HO-1 in I/R-induced hepatic injury focusing on mitochondrial QC associated with PGAM5 signaling...
March 7, 2018: Life Sciences
Fei Hong, Lu Wan, Jie Liu, Ke Huang, Zhenmeng Xiao, Yingjing Zhang, Chunwei Shi
Liver fibrosis is characterized by deposition of excessive extracellular matrix (ECM). The major source of ECM is activated hepatic stellate cells (HSCs). Previously, we reported that hypoxia-inducible factor-1 (Hif-1) regulates activation of HSCs through autophagy. In current work, human HSC cell line LX-2 was used as cell model. It was determined that trimethylation of H3 histone on lysine 4 (H3K4me3) occurred in the Hif-1 transcriptional complex. Inhibition of modifications of histone methylation suppressed Hif-1 nuclear transport, autophagosome formation, and activation of LX-2 cells...
March 2018: FEBS Open Bio
Timothy D Girard, Jennifer L Thompson, Pratik P Pandharipande, Nathan E Brummel, James C Jackson, Mayur B Patel, Christopher G Hughes, Rameela Chandrasekhar, Brenda T Pun, Leanne M Boehm, Mark R Elstad, Richard B Goodman, Gordon R Bernard, Robert S Dittus, E W Ely
BACKGROUND: Delirium during critical illness results from numerous insults, which might be interconnected and yet individually contribute to long-term cognitive impairment. We sought to describe the prevalence and duration of clinical phenotypes of delirium (ie, phenotypes defined by clinical risk factors) and to understand associations between these clinical phenotypes and severity of subsequent long-term cognitive impairment. METHODS: In this multicentre, prospective cohort study, we included adult (≥18 years) medical or surgical ICU patients with respiratory failure, shock, or both as part of two parallel studies: the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study, and the Delirium and Dementia in Veterans Surviving ICU Care (MIND-ICU) study...
March 2018: Lancet Respiratory Medicine
Hiromu Miyake, Bo Li, Carol Lee, Yuhki Koike, Yong Chen, Shogo Seo, Agostino Pierro
BACKGROUND: Necrotizing enterocolitis (NEC) is a disease known to cause injury to multiple organs including the liver. Liver regeneration is essential for the recovery after NEC-induced liver injury. Our aim was to investigate hepatic proliferation and progenitor cell marker expression in experimental NEC. METHODS: Following ethical approval (#32238), NEC was induced in mice by hypoxia, gavage feeding of hyperosmolar formula, and lipopolysaccharide. Breastfed pups were used as control...
February 7, 2018: Journal of Pediatric Surgery
Huanhuan Jin, Naqi Lian, Mianli Bian, Chenxi Zhang, Xingran Chen, Jiangjuan Shao, Li Wu, Anping Chen, Qinglong Guo, Feng Zhang, Shizhong Zheng
Accumulating data reveal that oroxylin A has beneficial effects against chronic liver disease. The previously studies showed oroxylin A, a flavonoid extracted from Scutellariae radix, improved acute liver injury and accelerated liver regeneration in vivo. However, it's unclear that the effect of oroxylin A on alcoholic liver disease. The present study was aimed at elucidating the effect of oroxylin A on alcohol-induced hepatic steatosis and the underlying mechanisms. Human hepatocyte LO2 were cultured and stimulated with ethanol for inducing LO2 damage...
February 21, 2018: Chemico-biological Interactions
Zhen Li, Qian Ding, Li-Ping Ling, Ying Wu, Dong-Xiao Meng, Xiao Li, Chun-Qing Zhang
AIM: To investigate the effect of metformin on activated hepatic stellate cells (HSCs) and the possible signaling pathways involved. METHODS: A fibrotic mouse model was generated by intraperitoneal injection of carbon tetrachloride (CCl4 ) and subsequent treatment with or without metformin. The level of fibrosis was detected by hematoxylin-eosin staining, Sirius Red staining, and immunohistochemistry. The HSC cell line LX-2 was used for in vitro studies. The effect of metformin on cell proliferation (CCK8 assay), motility (scratch test and Transwell assay), contraction (collagen gel contraction assay), extracellular matrix (ECM) secretion (Western blot), and angiogenesis (ELISA and tube formation assay) was investigated...
February 21, 2018: World Journal of Gastroenterology: WJG
Bimit Mahat, Étienne Chassé, Clare Lindon, Jean-François Mauger, Pascal Imbeault
Circulating fatty acids are a major systemic energy source in the fasting state as well as a determinant of hepatic triglyceride (TG)-rich very low-density lipoprotein (VLDL) production. Upon acute hypoxia, sympathetic arousal induces adipose tissue lipolysis, resulting in an increase in circulating non-esterified fatty acids (NEFA). Animal studies suggest that TG clearance may also be strongly reduced under hypoxia, though this effect has been shown to be dependent on temperature. Whether the hypoxia-induced rise in blood fatty acid concentrations effects fasting TG levels in humans under thermoneutral conditions remains unknown...
February 21, 2018: Applied Physiology, Nutrition, and Metabolism, Physiologie Appliquée, Nutrition et Métabolisme
Rebecca D Powell, Donna A Goodenow, A Britton Christmas, Iain H Mckillop, Susan L Evans
Conditions of systemic stress can lead to increased reactive oxygen species production, mitochondrial dysfunction, systemic inflammation, and multiorgan dysfunction. Triphenylphosphonium (TPP+) is a lipophilic cation used to target therapeutics to mitochondria. We sought to determine the effects of TPP+ on mitochondrial integrity. Male rats were anesthetized and TPP+ (5 mg/kg) or vehicle (saline) was administered intravenously 30-minutes after anesthesia initiation and intraperitoneally (20 mg/kg) 60-minutes later...
January 1, 2018: American Surgeon
Yi Sun, Yang Wang, Liang Zhou, Yizhou Zou, Gengwen Huang, Ge Gao, Shi Ting, Xiong Lei, Xiang Ding
Mesenchymal stem cell (MSC) transplantation is a promising treatment for ischemia-reperfusion injury (IRI). However, its effects on hepatic IRI were not consistent in the previous studies. 3D spheroid-cultured MSCs enhance their production of trophic and anti-inflammatory properties, but their effects on hepatic IRI remain unclear. In this study, we compared the 3D spheroid-cultured human umbilical derived MSCs (3D UC-MSCs) with 2D-cultured UC-MSCs (2D UC-MSCs) on treating hepatic IRI. The RNA sequencing data showed that suppression of cell mitosis, response to hypoxia, inflammation, and angiogenesis were the top genetic changes in 3D UC-MSCs compared with 2D UC-MSCs...
February 6, 2018: Scientific Reports
Joseph Bledsoe, Scott Woller, Scott Stevens, Valerie Aston, Rich Patten, Todd Allen, Benjamin Horne, Lydia Dong, James Lloyd, Greg Snow, Troy Madsen, Gregory Elliott
BACKGROUND: The efficacy and safety of managing patients with low-risk pulmonary embolism (PE) without hospitalization requires objective data from US medical centers. We sought to determine the 90-day composite rate of recurrent symptomatic venous thromboembolism (VTE), major bleeding events, and all-cause mortality among consecutive patients diagnosed with acute low-risk PE managed without inpatient hospitalization; and to measure patient satisfaction. METHODS: We performed a prospective cohort single-arm management study conducted from January 2013 to October 2016 in five emergency departments...
February 1, 2018: Chest
Martien van Wenum, Aziza A A Adam, Vincent A van der Mark, Jung-Chin Chang, Manon E Wildenberg, Erik J Hendriks, Aldo Jongejan, Perry D Moerland, Thomas M van Gulik, Ronald P Oude Elferink, Robert A F M Chamuleau, Ruurdtje Hoekstra
The in vitro generation of terminally differentiated hepatocytes is an unmet need. We investigated the contribution of oxygen concentration to differentiation in human liver cell lines HepaRG and C3A. HepaRG cells were cultured under hypoxia (5%O2), normoxia (21%O2) or hyperoxia (40%O2). Cultures were analysed for hepatic functions, gene transcript levels, and protein expression of albumin, hepatic transcription factor CEBPα, hepatic progenitor marker SOX9, and hypoxia inducible factor (HIF)1α. C3A cells were analysed after exposure to normoxia or hyperoxia...
February 4, 2018: Journal of Cell Communication and Signaling
A-Rum Yoon, JinWoo Hong, Minjung Kim, Chae-Ok Yun
Cancer-specific promoter driven replication of oncolytic adenovirus (Ad) is cancer-specific, but shows low transcriptional activity. Thus, we generated several chimeric α-fetoprotein (AFP) promoter variants, containing reconstituted enhancer and silencer regions, to preferentially drive Ad replication in hepatocellular carcinoma (HCC). Modified AFP promoter, containing 2 enhancer A regions and a single enhancer B region (a2bm), showed strong and HCC-specific transcription. In AFP-positive HCCs, gene expression was 43- to 456-fold higher than those of control AFP promoter lacking enhancers...
February 2, 2018: Scientific Reports
Ajaikumar B Kunnumakkara, Bethsebie L Sailo, Kishore Banik, Choudhary Harsha, Sahdeo Prasad, Subash Chandra Gupta, Alok Chandra Bharti, Bharat B Aggarwal
Extensive research within the last several decades has revealed that the major risk factors for most chronic diseases are infections, obesity, alcohol, tobacco, radiation, environmental pollutants, and diet. It is now well established that these factors induce chronic diseases through induction of inflammation. However, inflammation could be either acute or chronic. Acute inflammation persists for a short duration and is the host defense against infections and allergens, whereas the chronic inflammation persists for a long time and leads to many chronic diseases including cancer, cardiovascular diseases, neurodegenerative diseases, respiratory diseases, etc...
January 25, 2018: Journal of Translational Medicine
Cen Xie, Xiaoxia Gao, Dongxu Sun, Youbo Zhang, Kristopher W Krausz, Xuemei Qin, Frank Gonzalez
PT2385 is a first-in-class, selective small molecule inhibitor of hypoxia inducible factor-2α (HIF-2α) developed for the treatment of advanced clear cell renal cell carcinoma. Preclinical results demonstrated that PT2385 has potent anti-tumor efficacy in mouse xenograft models of kidney cancer. It also has activity toward metabolic disease in a mouse model. However, no metabolism data is currently publicly available. It is of great importance to characterize the metabolism of PT2385 and identify its effect on systemic homeostasis in mice...
January 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Andrea Ferrigno, Clarissa Berardo, Laura Giuseppina Di Pasqua, Veronica Siciliano, Plinio Richelmi, Ferdinando Nicoletti, Mariapia Vairetti
2-Methyl-6-(phenylethynyl)pyridine (MPEP), a negative allosteric modulator of the metabotropic glutamate receptor (mGluR) 5, protects hepatocytes from ischemic injury. In astrocytes and microglia, MPEP depletes ATP. These findings seem to be self-contradictory, since ATP depletion is a fundamental stressor in ischemia. This study attempted to reconstruct the mechanism of MPEP-mediated ATP depletion and the consequences of ATP depletion on protection against ischemic injury. We compared the effects of MPEP and other mGluR5 negative modulators on ATP concentration when measured in rat hepatocytes and acellular solutions...
January 23, 2018: International Journal of Molecular Sciences
Denise Van der Graaff, Wilhelmus J Kwanten, Filip J Couturier, Jesse S Govaerts, Wim Verlinden, Isabel Brosius, Michiel D'Hondt, Ann Driessen, Benedicte Y De Winter, Joris G De Man, Peter P Michielsen, Sven M Francque
Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. The presence of portal hypertension has been demonstrated in NAFLD prior to development of inflammation or fibrosis, and is a result of extrahepatic and intrahepatic factors, principally driven by vascular dysfunction. An increased intrahepatic vascular resistance potentially contributes to progression of NAFLD via intralobular hypoxia. However, the exact mechanisms underlying vascular dysfunction in NAFLD remain unknown...
January 11, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
Md Saydur Rahman, Peter Thomas
Although marine and coastal environments which are contaminated with xenobiotic organic compounds often become hypoxic during the summer, the interactive effects of hypoxia and xenobiotic exposure on marine species such as teleost fishes remain poorly understood. The expression and activity of monooxygenase enzyme cytochrome P450-1A (CYP1A) in fishes are upregulated by exposure to polychlorinated biphenyls (PCBs), whereas they are down-regulated during hypoxia exposure. We investigated the interactive effects of hypoxia and PCB co-exposure on hepatic CYP1A expression in Atlantic croaker and on potential regulators of CYP1A...
January 8, 2018: Environmental Toxicology
Yanyang Li, Chunyan Lou, Weiying Wang
Hepatic ischemia reperfusion (I/R) injury is unavoidable in various clinical conditions. Despite considerable investigation, the underlying molecular mechanism revealing liver I/R injury remains elusive. Stromal interaction molecule 1 (STIM1) plays essential role in regulating the induction of cellular responses to a number of stress conditions, including temperature changes, elevated ROS, and hypoxia. Here, to explore if STIM1 is involved in hepatic injury, wild type (WT) and STIM1-knockout (STIM1-/-) mice were subjected to I/R...
January 3, 2018: Biochemical and Biophysical Research Communications
Bang Xiao, Shiyong Wang, Guoshi Yang, Xiaoxi Sun, Shanmin Zhao, Lifang Lin, Jishuai Cheng, Wenjing Yang, Wei Cong, Wei Sun, Guanghan Kan, Shufang Cui
Background/Aims: Naked mole rats (NMRs) spend their lives in burrow systems containing very low levels of oxygen, indicating long-term hypoxic exposure, and suggesting that pathological changes caused by hypoxia are attenuated or absent in this hypoxia-tolerant species. The mechanisms underlying NMRs hypoxia tolerance remain poorly understood. In this study, we explored whether hypoxia inducible factor 1α (HIF-1α), and vascular endothelial growth factor A (VEGFA) play a role in NMRs adaption to hypoxia...
December 15, 2017: Oncotarget
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