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Andrew Holowiecki, Britton O'Shields, Matthew J Jenny
Heme oxygenase 1 (HMOX1) degrades heme into biliverdin, which is subsequently converted to bilirubin by biliverdin reductase (BVRa or BVRb) in a manner analogous to the classic anti-oxidant glutathione-recycling pathway. To gain a better understanding of the potential antioxidant roles the BVR enzymes may play during development, the spatiotemporal expression and transcriptional regulation of zebrafish hmox1a, bvra and bvrb were characterized under basal conditions and in response to pro-oxidant exposure. All three genes displayed spatiotemporal expression patterns consistent with classic hematopoietic progenitors during development...
October 17, 2016: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
Daniel Hanna, Ariane Emami Riedmaier, Kim S Sugamori, Denis M Grant
The incidence of liver cancer is higher in men than in women. This sex difference is also observed in murine tumor induction models that result in the appearance of liver tumors in adult mice following their exposure on postnatal days 8 and/or 15 to carcinogens such as 4-aminobiphenyl (ABP) or diethylnitrosamine (DEN). Previous studies performed in adult mice showed that acute hepatotoxic and inflammatory responses to high-dose DEN exposure were greater in males than in females, leading to the suggestion that these responses could account for the sex difference in tumor development...
October 13, 2016: Toxicology
Kristy Na Kubícková, Iva Subhanová, Renáta Konícková, Linda Matousová, Petr Urbánek, Hana Parobková, Martin Kupec, Jirí Pudil, Libor Vítek
:  Introduction and aim. Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor. It is primarily caused by hepatic cirrhosis or chronic viral hepatitis. Hepatic carcinogenesis is associated with increased oxidative stress. Thus, the aim of our study was to assess expression of the genes involved in the homeostasis of oxidative stress in patients with HCC. MATERIAL AND METHODS: The study was performed on 32 patients with primary HCC (verified by liver histology in 29 patients) and 27 control subjects (in 11 subjects, liver histology was available either with no or minimal changes in the liver tissue)...
November 2016: Annals of Hepatology
Hailong Song, Yuan Lu, Zhe Qu, Valeri V Mossine, Matthew B Martin, Jie Hou, Jiankun Cui, Brenda A Peculis, Thomas P Mawhinney, Jianlin Cheng, C Michael Greenlief, Kevin Fritsche, Francis J Schmidt, Ronald B Walter, Dennis B Lubahn, Grace Y Sun, Zezong Gu
Aged garlic extract (AGE) is widely used as a dietary supplement on account of its protective effects against oxidative stress and inflammation. But less is known about specific molecular targets of AGE and its bioactive components, including N-α-(1-deoxy-D-fructos-1-yl)-L-arginine (FruArg). Our recent study showed that both AGE and FruArg significantly attenuate lipopolysaccharide (LPS)-induced neuroinflammatory responses in BV-2 microglial cells. This study aims to unveil effects of AGE and FruArg on gene expression regulation in LPS stimulated BV-2 cells...
October 13, 2016: Scientific Reports
Andrew Holowiecki, Britton O'Shields, Matthew J Jenny
While heme is an important cofactor for numerous proteins, it is highly toxic in its unbound form and can perpetuate the formation of reactive oxygen species. Heme oxygenase enzymes (HMOX1 and HMOX2) degrade heme into biliverdin and carbon monoxide, with biliverdin subsequently being converted to bilirubin by biliverdin reductase (BVRa or BVRb). As a result of the teleost-specific genome duplication event, zebrafish have paralogs of hmox1 (hmox1a and hmox1b) and hmox2 (hmox2a and hmox2b). Expression of all four hmox paralogs and two bvr isoforms were measured in adult tissues (gill, brain and liver) and sexually dimorphic differences were observed, most notably in the basal expression of hmox1a, hmox2a, hmox2b and bvrb in liver samples...
September 23, 2016: Toxicology and Applied Pharmacology
Maria G Detsika, Pu Duann, Vassilios Atsaves, Apostolos Papalois, Elias A Lianos
Complement-activation controllers, including decay accelerating factor (DAF), are gaining emphasis as they minimize injury in various dysregulated complement-activation disorders, including glomerulopathies. Heme oxygenase (HO)-1 overexpression or induction has been shown to attenuate injury in complement-dependent models of glomerulonephritis. This study investigated whether up-regulation of DAF by heme oxygenase 1 (HO-1) is an underlying mechanism by using Hmox-1-deficient rats (Hmox1(+/-); Hmox1(-/-)) or rats with Hmox-1 overexpression targeted to glomerular epithelial cells (GEC(Hmox-1)), which are particularly vulnerable to complement-mediated injury owing to their terminally differentiated nature...
September 20, 2016: American Journal of Pathology
Yuan Gao, Zhijun Cao, Xi Yang, Mohamed A Abdelmegeed, Jinchun Sun, Si Chen, Richard D Beger, Kelly Davis, William F Salminen, Byoung-Joon Song, Donna L Mendrick, Li-Rong Yu
Overdose of acetaminophen (APAP) is a major cause of acute liver failure. To identify pathways related to hepatotoxicity and potential biomarkers of liver injury, a proteomic approach of (16) O/(18) O labeling and 2D-LC-MS/MS was used to analyze liver tissues from rats at 6 and 24 h post-treatment with low (100 mg/kg) and high (1250 mg/kg) doses of APAP. The analysis revealed that molecular pathways evolved progressively from scattered and less significant perturbations to more focused and significant alterations in a dose- and time-dependent manner...
September 16, 2016: Proteomics. Clinical Applications
Chase R Williams, James W MacDonald, Theo K Bammler, Michael H Paulsen, Christopher D Simpson, Evan P Gallagher
Salmon exposed to waterborne metals can experience olfactory impairment leading to disrupted chemosensation. In the current study, we investigated the effects of cadmium (Cd) on salmon olfactory function by modeling an exposure scenario where juvenile salmon transiently migrate through a polluted waterway. Coho were exposed to environmentally-relevant concentrations of waterborne Cd (2 and 30 μg/L) for 48 hrs and (0.3 and 2 μg/L) for 16 days, followed by a 16-day depuration associated with outmigration. Cadmium exposures inhibited behavioral responses towards L-cysteine and conspecific odorants, with effects persisting following the depuration...
September 11, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Robert H LeBlanc, Ruiya Chen, Magdy H Selim, Khalid A Hanafy
BACKGROUND: Subarachnoid hemorrhage (SAH) is a devastating disease that affects over 30,000 Americans per year. Previous animal studies have explored the therapeutic effects of deferoxamine (DFX) via its iron-chelating properties after SAH, but none have assessed the necessity of microglial/macrophage heme oxygenase-1 (HO-1 or Hmox1) in DFX neuroprotection, nor has the efficacy of an intracerebroventricular (ICV) administration route been fully examined. We explored the therapeutic efficacy of systemic and ICV DFX in a SAH mouse model and its effect on microglial/macrophage HO-1...
2016: Journal of Neuroinflammation
Anita Ayer, Abolfazl Zarjou, Anupam Agarwal, Roland Stocker
Heme oxygenases are composed of two isozymes, Hmox1 and Hmox2, that catalyze the degradation of heme to carbon monoxide (CO), ferrous iron, and biliverdin, the latter of which is subsequently converted to bilirubin. While initially considered to be waste products, CO and biliverdin/bilirubin have been shown over the last 20 years to modulate key cellular processes, such as inflammation, cell proliferation, and apoptosis, as well as antioxidant defense. This shift in paradigm has led to the importance of heme oxygenases and their products in cell physiology now being well accepted...
October 2016: Physiological Reviews
Ning Ding, Xin Wang, Marc G Weisskopf, David Sparrow, Joel Schwartz, Howard Hu, Sung Kyun Park
BACKGROUND: Cumulative exposure to lead is associated with cardiovascular outcomes. Polymorphisms in the δ-aminolevulinic acid dehydratase (ALAD), hemochromatosis (HFE), heme oxygenase-1 (HMOX1), vitamin D receptor (VDR), glutathione S-transferase (GST) supergene family (GSTP1, GSTT1, GSTM1), apolipoprotein E (APOE),angiotensin II receptor-1 (AGTR1) and angiotensinogen (AGT) genes, are believed to alter toxicokinetics and/or toxicodynamics of lead. OBJECTIVES: We assessed possible effect modification by genetic polymorphisms in ALAD, HFE, HMOX1, VDR, GSTP1, GSTT1, GSTM1, APOE, AGTR1 and AGT individually and as the genetic risk score (GRS) on the association between cumulative lead exposure and incident coronary heart disease (CHD) events...
2016: PloS One
Haranatha Reddy Potteti, Chandramohan Reddy Tamatam, Rakesh Marreddy, Narsa M Reddy, Sanjeev Noel, Hamid Rabb, Sekhar P Reddy
Ischemia-reperfusion (IR)-induced kidney injury is a major clinical problem, but the underlying mechanisms remain unclear. The transcription factor Nuclear Factor, Erythroid 2-like 2 (NFE2L2 or Nrf2) is crucial for protection against oxidative stress generated by pro-oxidant insults. We have previously shown that Nrf2 deficiency enhances susceptibility to IR-induced kidney injury in mice and its upregulation is protective. Here, we examined Nrf2 target antioxidant gene expression and the mechanisms of its activation in both human and murine kidney epithelia following acute (2 h) and chronic (12 h) hypoxia and re-oxygenation conditions...
August 31, 2016: American Journal of Physiology. Renal Physiology
Min Li, Suzette Riddle, Hui Zhang, Angelo D'Alessandro, Amanda Flockton, Natalie J Serkova, Kirk C Hansen, Radu Moldvan, B Alexandre McKeon, Maria Frid, Sushil Kumar, Hong Li, Hongbing Liu, Angela Caánovas, Juan F Medrano, Milton G Thomas, Dijana Iloska, Lydie Plecitá-Hlavatá, Petr Ježek, Soni Pullamsetti, Mehdi A Fini, Karim C El Kasmi, QingHong Zhang, Kurt R Stenmark
BACKGROUND: Changes in metabolism have been suggested to contribute to the aberrant phenotype of vascular wall cells, including fibroblasts, in pulmonary hypertension (PH). Here, we test the hypothesis that metabolic reprogramming to aerobic glycolysis is a critical adaptation of fibroblasts in the hypertensive vessel wall that drives proliferative and proinflammatory activation through a mechanism involving increased activity of the NADH-sensitive transcriptional corepressor C-terminal binding protein 1 (CtBP1)...
October 11, 2016: Circulation
Rowena Schultz, Otto W Witte, Christian Schmeer
PURPOSE: The mitochondrial protein frataxin (FXN) is highly expressed in metabolically active tissues and has been shown to improve cell survival in response to oxidative stress after ischemia. Retinal ischemia/hypoxia is a complication of ocular diseases such as diabetic retinopathy and glaucoma. There are no effective therapeutic approaches currently available. This study was performed to evaluate the neuroprotective effects of FXN after acute retinal ischemia/reperfusion in vivo. METHODS: Retinal ischemia/reperfusion was induced in adult wild-type and FXN-overexpressing mice by transient elevation of intraocular pressure (IOP) for 45 minutes...
August 1, 2016: Investigative Ophthalmology & Visual Science
Nóra Faragó, Ágnes Katalin Kocsis, Csilla Braskó, Sándor Lovas, Márton Rózsa, Judith Baka, Balázs Kovács, Katalin Mikite, Viktor Szemenyei, Gábor Molnár, Attila Ozsvár, Gáspár Oláh, Ildikó Piszár, Ágnes Zvara, Attila Patócs, Pál Barzó, László G Puskás, Gábor Tamás
Functional and molecular changes associated with pathophysiological conditions are relatively easily detected based on tissue samples collected from patients. Population specific cellular responses to disease might remain undiscovered in samples taken from organs formed by a multitude of cell types. This is particularly apparent in the human cerebral cortex composed of a yet undefined number of neuron types with a potentially different involvement in disease processes. We combined cellular electrophysiology, anatomy and single cell digital PCR in human neurons identified in situ for the first time to assess mRNA expression and corresponding functional changes in response to edema and increased intracranial pressure...
2016: Acta Neuropathologica Communications
Esther Dalko, Delphine Genete, Florent Auger, Claire Dovergne, Claire Lambert, Fabien Herbert, Pierre-André Cazenave, Jacques Roland, Sylviane Pied
Cerebral malaria is the deadliest complication of Plasmodium falciparum infection. Its pathophysiology is associated with a strong pro-inflammatory reaction and the activation of glial cells. Among modulators released during the infection, heme seems to play a controversial role in the pathophysiology of malaria. Herein, we first investigated the phenotype of glial cells during cerebral malaria in C57BL/6 mice infected with P. berghei ANKA. Given the fact that high levels of heme were associated with cerebral malaria, we then investigated its impact on microglial, astrocyte, and T cell responses to further clarify its contribution in the neuropathophysiology...
November 2016: Brain, Behavior, and Immunity
Haiying Chen, Hongli Yang, Chong Xu, Hongmei Yue, Peng Xia, Pádraig Michael Strappe, Lei Wang, Li Pan, Wenqiang Tang, Shuangfeng Chen, Lexin Wang
BACKGROUND: Pulmonary arterial hypertension (PAH) is associated with sustained vasoconstriction, inflammation and suppressed apoptosis of smooth muscle cells. Our previous studies have found that rat bone marrow-derived mesenchymal stem cells (rBMSCs) transduced with a mutant caveolin-1(F92A-Cav1) could enhance endothelial nitric oxide synthase (eNOS) activity and improve pulmonary vascular remodeling, but the potential mechanism is not yet fully explored. The present study was to investigate the gene expression profile upon rBMSCs/F92A-Cav1delivered to PAH rat to evaluate the role of F92A-Cav1 in its regulation...
June 23, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Richard Ramsden, Evan P Gallagher
The transcription factor NFE2L2 (Nuclear Factor, Erythroid 2-Like 2, or NRF2) plays a key role in maintaining the redox state within cells. Characterization of this pathway has extended to fish, most notably zebrafish (Danio rerio), in which two paralogs of the transcription factor exist: Nrf2a, an activator, and Nrf2b, a negative regulator during embryogenesis. Only one ARE target has been thoroughly delineated in zebrafish, and this deviated from the canonical sequence derived from studies in mammals. In general, the mechanistic pathway has not been characterized in non-model aquatic organisms that are commonly exposed to environmental pollutants...
July 6, 2016: Redox Biology
M L Perepechaeva, N G Kolosova, N A Stefanova, A Zh Fursova, A Y Grishanova
Age-related macular degeneration (AMD) is a complex multifactorial disease of the elderly, with unclear pathogenesis; AMD is the leading cause of blindness. One of the destructive processes in AMD is oxidative stress, which leads to an imbalance in the processes responsible for production and detoxification of reactive oxygen species. The aryl hydrocarbon receptor (AhR) signaling pathway can participate in the development of oxidative stress, but the main regulator of antioxidant defense is nuclear factor, erythroid derived 2 (Nrf2)...
August 2016: Experimental and Molecular Pathology
Radim Vrzal, Peter Illes, Zdenek Dvorak
BACKGROUND: We carried out a test whether or not transplant drugs such as cyclosporine A, Rapamycin (Sirolimus), Tacrolimus, Everolimus and Mycophenolate mofetil affects the expression of phase II enzymes comprising of UDP-glucuronosyltransferases (UGTs) and glutathione-S-transferases (GSTs), and antioxidant enzymes that consist of glutathione reductase (GSR), glutathione peroxidase 1 (GPX1) and heme-oxygenase 1 (HMOX1). METHODS: Experiments were performed in primary cultures of human hepatocytes and in human hepatocarcinoma HepG2 cells, the models of metabolically competent and incompetent cells, respectively...
October 2016: Pharmacological Reports: PR
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