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Suliman, Hagir B.

Overview:

Dr. Suliman is an expert in the molecular and cell biology of mammalian diseases, particularly in the molecular regulation of oxidant inflammatory responses in the heart and lung. She has a strong interest and expertise in the transcriptional control of cell metabolism, especially mitochondrial biogenesis and mitochondrial-mediated apoptosis and necrosis. Her recent publications have focused on the redox-regulation of nuclear transcription factors involved in both mitochondrial biogenesis and cellular adaptation to oxidative and nitrosative stress. Specifically, she has undertaken promoter analyses of nuclear respiratory factors-1 and -2 that indicate that these transcription factor genes are controlled by redox-regulated signaling networks activated by reactive oxygen and nitrogen species, and carbon monoxide. Dr. Suliman and her colleagues have reported that the cancer chemotherapeutic, doxorubicin, disrupts cardiac mitochondrial biogenesis through mitochondrial oxidant production, which promotes intrinsic apoptosis, while heme oxygenase-1 up-regulates adaptive mitochondrial biogenesis and opposes apoptosis through close regulation of mitochondrial ROS signaling by physiological CO production, thus forestalling fibrosis and cardiomyopathy. Most recently I have been defining the role of mitochondrial transcription factors in regulating cell survival, proliferation and differentiation including in embryonic stem cells and pluripotent cells.

Positions:

Associate Professor in Anesthesiology

Anesthesiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1996

Ph.D. — Virginia Polytech Institute and State University

Grants:

Mitochondrial quality control and alveolar damage resolution after acute lung injury

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 10, 2017
End Date
June 30, 2021

Redox Regulation of Lung Mitochondrial Biogenesis in Sepsis/Pneumonia

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 01, 2012
End Date
June 30, 2017

Project 2: Regulation of Mitochondrial Quality Control by Heme Oxygenase-1 System in Sepsis

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
Brigham and Women's Hospital
Role
Co Investigator
Start Date
August 15, 2011
End Date
June 30, 2017

Nitric oxide and mitochondrial biogenesis in sepsis

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
December 15, 2005
End Date
January 31, 2014

Regulation of mitochondrial biogenesis by heme oxygenase-1

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 14, 2008
End Date
April 30, 2013

Mitochondrial biogenesis in sepsis-induced organ dysfunction

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 01, 2009
End Date
January 31, 2013

Lung Injury Protection by Coagulation Blockade

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 15, 2005
End Date
June 30, 2010

IPA - Hagir Suliman

Administered By
Anesthesiology
AwardedBy
Veterans Administration Medical Center
Role
Assistant Research Professor
Start Date
May 01, 2006
End Date
April 30, 2008

Developmental neurotoxicity in Offspring Following Combined Maternal Exposure to Nocotine and Chlorpyrifo

Administered By
Pharmacology & Cancer Biology
AwardedBy
Environmental Protection Agency
Role
Research Associate
Start Date
September 01, 2001
End Date
February 28, 2005
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Publications:

Mitochondrial quality control in alveolar epithelial cells damaged by S. aureus pneumonia in mice.

Mitochondrial damage is often overlooked in acute lung injury (ALI), yet most of the lung's physiological processes, such as airway tone, mucociliary clearance, ventilation-perfusion (Va/Q) matching, and immune surveillance require aerobic energy provision. Because the cell's mitochondrial quality control (QC) process regulates the elimination and replacement of damaged mitochondria to maintain cell survival, we serially evaluated mitochondrial biogenesis and mitophagy in the alveolar regions of mice in a validated Staphylococcus aureus pneumonia model. We report that apart from cell lysis by direct contact with microbes, modest epithelial cell death was detected despite significant mitochondrial damage. Cell death by TdT-mediated dUTP nick-end labeling staining occurred on days 1 and 2 postinoculation: apoptosis shown by caspase-3 cleavage was present on days 1 and 2, while necroptosis shown by increased levels of phospho- mixed lineage kinase domain-like protein (MLKL) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1) was present on day 1 Cell death in alveolar type I (AT1) cells assessed by bronchoalveolar lavage fluid receptor for advanced glycation end points (RAGE) levels was high, yet AT2 cell death was limited while both mitochondrial biogenesis and mitophagy were induced. These mitochondrial QC mechanisms were evaluated mainly in AT2 cells by localizing increases in citrate synthase content, increases in nuclear mitochondrial biogenesis regulators nuclear respiratory factor-1 (NRF-1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and increases in light chain 3B protein (LC3-I)/LC3II ratios. Concomitant changes in p62, Pink 1, and Parkin protein levels indicated activation of mitophagy. By confocal microscopy, mitochondrial biogenesis and mitophagy were often observed on day 1 within the same AT2 cells. These findings imply that mitochondrial QC activation in pneumonia-damaged AT2 cells promotes cell survival in support of alveolar function.

Authors
Suliman, HB; Kraft, B; Bartz, R; Chen, L; Welty-Wolf, KE; Piantadosi, CA
MLA Citation
Suliman, HB, Kraft, B, Bartz, R, Chen, L, Welty-Wolf, KE, and Piantadosi, CA. "Mitochondrial quality control in alveolar epithelial cells damaged by S. aureus pneumonia in mice." American journal of physiology. Lung cellular and molecular physiology 313.4 (October 2017): L699-L709.
PMID
28663335
Source
epmc
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
313
Issue
4
Publish Date
2017
Start Page
L699
End Page
L709
DOI
10.1152/ajplung.00197.2017

Mitochondrial quality-control dysregulation in conditional HO-1(-/-) mice.

The heme oxygenase-1 (Hmox1; HO-1) pathway was tested for defense of mitochondrial quality control in cardiomyocyte-specific Hmox1 KO mice (HO-1[CM](-/-)) exposed to oxidative stress (100% O2). After 48 hours of exposure, these mice showed persistent cardiac inflammation and oxidative tissue damage that caused sarcomeric disruption, cardiomyocyte death, left ventricular dysfunction, and cardiomyopathy, while control hearts showed minimal damage. After hyperoxia, HO-1(CM)(-/-) hearts showed suppression of the Pgc-1α/nuclear respiratory factor-1 (NRF-1) axis, swelling, low electron density mitochondria by electron microscopy (EM), increased cell death, and extensive collagen deposition. The damage mechanism involves structurally deficient autophagy/mitophagy, impaired LC3II processing, and failure to upregulate Pink1- and Park2-mediated mitophagy. The mitophagy pathway was suppressed through loss of NRF-1 binding to proximal promoter sites on both genes. These results indicate that cardiac Hmox1 induction not only prevents heme toxicity, but also regulates the timing and registration of genetic programs for mitochondrial quality control that limit cell death, pathological remodeling, and cardiac fibrosis.

Authors
Suliman, HB; Keenan, JE; Piantadosi, CA
MLA Citation
Suliman, HB, Keenan, JE, and Piantadosi, CA. "Mitochondrial quality-control dysregulation in conditional HO-1(-/-) mice. (Published online)" JCI Insight 2.3 (February 9, 2017): e89676-.
PMID
28194437
Source
pubmed
Published In
JCI insight
Volume
2
Issue
3
Publish Date
2017
Start Page
e89676
DOI
10.1172/jci.insight.89676

Mitochondrial Dysfunction in Lung Pathogenesis.

Remarkable new roles for mitochondria in calcium handling, apoptosis, heme turnover, inflammation, and oxygen and nutrient sensing have been discovered for organelles that were once thought to be simple energy converters. Although deficits in mitochondrial function are often associated with energy failure and apoptosis, working cells maintain a mitochondrial reserve that affords the organelles distinct homeostatic sensing and regulatory abilities in lung cells. As primary intracellular sources of oxidants, mitochondria serve as critical monitors and modulators of vital oxidation-reduction processes, including mitochondrial biogenesis, mitophagy, inflammasome activation, cell proliferation, and prevention of fibrosis. These processes participate in disease pathogenesis in all lung regions mainly when interference with mitochondrial quality control mechanisms impedes their roles in maintenance of lung health. Sharper identification of mitochondrial-driven signaling mechanisms in specific lung cell types will better refine our understanding of respiratory disease pathogenesis and lead to new diagnostic and therapeutic measures to support mitochondrial quality.

Authors
Piantadosi, CA; Suliman, HB
MLA Citation
Piantadosi, CA, and Suliman, HB. "Mitochondrial Dysfunction in Lung Pathogenesis." Annual review of physiology 79 (February 2017): 495-515. (Review)
PMID
27959621
Source
epmc
Published In
Annual Review of Physiology
Volume
79
Publish Date
2017
Start Page
495
End Page
515
DOI
10.1146/annurev-physiol-022516-034322

Heme Oxygenase-1/Carbon Monoxide System and Embryonic Stem Cell Differentiation and Maturation into Cardiomyocytes.

AIMS: The differentiation of embryonic stem (ES) cells into energetically efficient cardiomyocytes contributes to functional cardiac repair and is envisioned to ameliorate progressive degenerative cardiac diseases. Advanced cell maturation strategies are therefore needed to create abundant mature cardiomyocytes. In this study, we tested whether the redox-sensitive heme oxygenase-1/carbon monoxide (HO-1/CO) system, operating through mitochondrial biogenesis, acts as a mechanism for ES cell differentiation and cardiomyocyte maturation. RESULTS: Manipulation of HO-1/CO to enhance mitochondrial biogenesis demonstrates a direct pathway to ES cell differentiation and maturation into beating cardiomyocytes that express adult structural markers. Targeted HO-1/CO interventions up- and downregulate specific cardiogenic transcription factors, transcription factor Gata4, homeobox protein Nkx-2.5, heart- and neural crest derivatives-expressed protein 1, and MEF2C. HO-1/CO overexpression increases cardiac gene expression for myosin regulatory light chain 2, atrial isoform, MLC2v, ANP, MHC-β, and sarcomere α-actinin and the major mitochondrial fusion regulators, mitofusin 2 and MICOS complex subunit Mic60. This promotes structural mitochondrial network expansion and maturation, thereby supporting energy provision for beating embryoid bodies. These effects are prevented by silencing HO-1 and by mitochondrial reactive oxygen species scavenging, while disruption of mitochondrial biogenesis and mitochondrial DNA depletion by loss of mitochondrial transcription factor A compromise infrastructure. This leads to failure of cardiomyocyte differentiation and maturation and contractile dysfunction. INNOVATION: The capacity to augment cardiomyogenesis via a defined mitochondrial pathway has unique therapeutic potential for targeting ES cell maturation in cardiac disease. CONCLUSION: Our findings establish the HO-1/CO system and redox regulation of mitochondrial biogenesis as essential factors in ES cell differentiation as well as in the subsequent maturation of these cells into functional cardiac cells.

Authors
Suliman, HB; Zobi, F; Piantadosi, CA
MLA Citation
Suliman, HB, Zobi, F, and Piantadosi, CA. "Heme Oxygenase-1/Carbon Monoxide System and Embryonic Stem Cell Differentiation and Maturation into Cardiomyocytes." Antioxid Redox Signal 24.7 (March 1, 2016): 345-360.
Website
http://hdl.handle.net/10161/13986
PMID
26725491
Source
pubmed
Published In
Antioxidants & Redox Signaling
Volume
24
Issue
7
Publish Date
2016
Start Page
345
End Page
360
DOI
10.1089/ars.2015.6342

Hypoxic Gene Expression of Donor Bronchi Linked to Airway Complications after Lung Transplantation.

Central airway stenosis (CAS) after lung transplantation has been attributed in part to chronic airway ischemia; however, little is known about the time course or significance of large airway hypoxia early after transplantation.To evaluate large airway oxygenation and hypoxic gene expression during the first month after lung transplantation and their relation to airway complications.Subjects who underwent lung transplantation underwent endobronchial tissue oximetry of native and donor bronchi at 0, 3, and 30 days after transplantation (n = 11) and/or endobronchial biopsies (n = 14) at 30 days for real-time polymerase chain reaction of hypoxia-inducible genes. Patients were monitored for 6 months for the development of transplant-related complications.Compared with native endobronchial tissues, donor tissue oxygen saturations (Sto2) were reduced in the upper lobes (74.1 ± 1.8% vs. 68.8 ± 1.7%; P < 0.05) and lower lobes (75.6 ± 1.6% vs. 71.5 ± 1.8%; P = 0.065) at 30 days post-transplantation. Donor upper lobe and subcarina Sto2 levels were also lower than the main carina (difference of -3.9 ± 1.5 and -4.8 ± 2.1, respectively; P < 0.05) at 30 days. Up-regulation of hypoxia-inducible genes VEGFA, FLT1, VEGFC, HMOX1, and TIE2 was significant in donor airways relative to native airways (all P < 0.05). VEGFA, KDR, and HMOX1 were associated with prolonged respiratory failure, prolonged hospitalization, extensive airway necrosis, and CAS (P < 0.05).These findings implicate donor bronchial hypoxia as a driving factor for post-transplantation airway complications. Strategies to improve airway oxygenation, such as bronchial artery re-anastomosis and hyperbaric oxygen therapy merit clinical investigation.

Authors
Kraft, BD; Suliman, HB; Colman, EC; Mahmood, K; Hartwig, MG; Piantadosi, CA; Shofer, SL
MLA Citation
Kraft, BD, Suliman, HB, Colman, EC, Mahmood, K, Hartwig, MG, Piantadosi, CA, and Shofer, SL. "Hypoxic Gene Expression of Donor Bronchi Linked to Airway Complications after Lung Transplantation." American journal of respiratory and critical care medicine 193.5 (March 2016): 552-560.
PMID
26488115
Source
epmc
Published In
American journal of respiratory and critical care medicine
Volume
193
Issue
5
Publish Date
2016
Start Page
552
End Page
560
DOI
10.1164/rccm.201508-1634oc

Mitochondrial Quality Control as a Therapeutic Target.

In addition to oxidative phosphorylation (OXPHOS), mitochondria perform other functions such as heme biosynthesis and oxygen sensing and mediate calcium homeostasis, cell growth, and cell death. They participate in cell communication and regulation of inflammation and are important considerations in aging, drug toxicity, and pathogenesis. The cell's capacity to maintain its mitochondria involves intramitochondrial processes, such as heme and protein turnover, and those involving entire organelles, such as fusion, fission, selective mitochondrial macroautophagy (mitophagy), and mitochondrial biogenesis. The integration of these processes exemplifies mitochondrial quality control (QC), which is also important in cellular disorders ranging from primary mitochondrial genetic diseases to those that involve mitochondria secondarily, such as neurodegenerative, cardiovascular, inflammatory, and metabolic syndromes. Consequently, mitochondrial biology represents a potentially useful, but relatively unexploited area of therapeutic innovation. In patients with genetic OXPHOS disorders, the largest group of inborn errors of metabolism, effective therapies, apart from symptomatic and nutritional measures, are largely lacking. Moreover, the genetic and biochemical heterogeneity of these states is remarkably similar to those of certain acquired diseases characterized by metabolic and oxidative stress and displaying wide variability. This biologic variability reflects cell-specific and repair processes that complicate rational pharmacological approaches to both primary and secondary mitochondrial disorders. However, emerging concepts of mitochondrial turnover and dynamics along with new mitochondrial disease models are providing opportunities to develop and evaluate mitochondrial QC-based therapies. The goals of such therapies extend beyond amelioration of energy insufficiency and tissue loss and entail cell repair, cell replacement, and the prevention of fibrosis. This review summarizes current concepts of mitochondria as disease elements and outlines novel strategies to address mitochondrial dysfunction through the stimulation of mitochondrial biogenesis and quality control.

Authors
Suliman, HB; Piantadosi, CA
MLA Citation
Suliman, HB, and Piantadosi, CA. "Mitochondrial Quality Control as a Therapeutic Target." Pharmacol Rev 68.1 (January 2016): 20-48. (Review)
Website
http://hdl.handle.net/10161/13988
PMID
26589414
Source
pubmed
Published In
Pharmacological reviews
Volume
68
Issue
1
Publish Date
2016
Start Page
20
End Page
48
DOI
10.1124/pr.115.011502

Heme oxygenase-1 regulates mitochondrial quality control in the heart.

The cardioprotective inducible enzyme heme oxygenase-1 (HO-1) degrades prooxidant heme into equimolar quantities of carbon monoxide, biliverdin, and iron. We hypothesized that HO-1 mediates cardiac protection, at least in part, by regulating mitochondrial quality control. We treated WT and HO-1 transgenic mice with the known mitochondrial toxin, doxorubicin (DOX). Relative to WT mice, mice globally overexpressing human HO-1 were protected from DOX-induced dilated cardiomyopathy, cardiac cytoarchitectural derangement, and infiltration of CD11b+ mononuclear phagocytes. Cardiac-specific overexpression of HO-1 ameliorated DOX-mediated dilation of the sarcoplasmic reticulum as well as mitochondrial disorganization in the form of mitochondrial fragmentation and increased numbers of damaged mitochondria in autophagic vacuoles. HO-1 overexpression promotes mitochondrial biogenesis by upregulating protein expression of NRF1, PGC1α, and TFAM, which was inhibited in WT animals treated with DOX. Concomitantly, HO-1 overexpression inhibited the upregulation of the mitochondrial fission mediator Fis1 and resulted in increased expression of the fusion mediators, Mfn1 and Mfn2. It also prevented dynamic changes in the levels of key mediators of the mitophagy pathway, PINK1 and parkin. Therefore, these findings suggest that HO-1 has a novel role in protecting the heart from oxidative injury by regulating mitochondrial quality control.

Authors
Hull, TD; Boddu, R; Guo, L; Tisher, CC; Traylor, AM; Patel, B; Joseph, R; Prabhu, SD; Suliman, HB; Piantadosi, CA; Agarwal, A; George, JF
MLA Citation
Hull, TD, Boddu, R, Guo, L, Tisher, CC, Traylor, AM, Patel, B, Joseph, R, Prabhu, SD, Suliman, HB, Piantadosi, CA, Agarwal, A, and George, JF. "Heme oxygenase-1 regulates mitochondrial quality control in the heart." JCI Insight 1.2 (2016): e85817-.
Website
http://hdl.handle.net/10161/13987
PMID
27110594
Source
pubmed
Published In
JCI insight
Volume
1
Issue
2
Publish Date
2016
Start Page
e85817
DOI
10.1172/jci.insight.85817

The HO-1/CO system regulates mitochondrial-capillary density relationships in human skeletal muscle.

The heme oxygenase-1 (HO-1)/carbon monoxide (CO) system induces mitochondrial biogenesis, but its biological impact in human skeletal muscle is uncertain. The enzyme system generates CO, which stimulates mitochondrial proliferation in normal muscle. Here we examined whether CO breathing can be used to produce a coordinated metabolic and vascular response in human skeletal muscle. In 19 healthy subjects, we performed vastus lateralis muscle biopsies and tested one-legged maximal O2 uptake (V̇o2max) before and after breathing air or CO (200 ppm) for 1 h daily for 5 days. In response to CO, there was robust HO-1 induction along with increased mRNA levels for nuclear-encoded mitochondrial transcription factor A (Tfam), cytochrome c, cytochrome oxidase subunit IV (COX IV), and mitochondrial-encoded COX I and NADH dehydrogenase subunit 1 (NDI). CO breathing did not increase V̇o2max (1.96 ± 0.51 pre-CO, 1.87 ± 0.50 post-CO l/min; P = not significant) but did increase muscle citrate synthase, mitochondrial density (139.0 ± 34.9 pre-CO, 219.0 ± 36.2 post-CO; no. of mitochondrial profiles/field), myoglobin content and glucose transporter (GLUT4) protein level and led to GLUT4 localization to the myocyte membrane, all consistent with expansion of the tissue O2 transport system. These responses were attended by increased cluster of differentiation 31 (CD31)-positive muscle capillaries (1.78 ± 0.16 pre-CO, 2.37 ± 0.59 post-CO; capillaries/muscle fiber), implying the enrichment of microvascular O2 reserve. The findings support that induction of the HO-1/CO system by CO not only improves muscle mitochondrial density, but regulates myoglobin content, GLUT4 localization, and capillarity in accordance with current concepts of skeletal muscle plasticity.

Authors
Pecorella, SRH; Potter, JVF; Cherry, AD; Peacher, DF; Welty-Wolf, KE; Moon, RE; Piantadosi, CA; Suliman, HB
MLA Citation
Pecorella, SRH, Potter, JVF, Cherry, AD, Peacher, DF, Welty-Wolf, KE, Moon, RE, Piantadosi, CA, and Suliman, HB. "The HO-1/CO system regulates mitochondrial-capillary density relationships in human skeletal muscle." American journal of physiology. Lung cellular and molecular physiology 309.8 (October 2015): L857-L871.
PMID
26186946
Source
epmc
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
309
Issue
8
Publish Date
2015
Start Page
L857
End Page
L871
DOI
10.1152/ajplung.00104.2015

Effects of inhaled CO administration on acute lung injury in baboons with pneumococcal pneumonia.

Inhaled carbon monoxide (CO) gas has therapeutic potential for patients with acute respiratory distress syndrome if a safe, evidence-based dosing strategy and a ventilator-compatible CO delivery system can be developed. In this study, we used a clinically relevant baboon model of Streptococcus pneumoniae pneumonia to 1) test a novel, ventilator-compatible CO delivery system; 2) establish a safe and effective CO dosing regimen; and 3) investigate the local and systemic effects of CO therapy on inflammation and acute lung injury (ALI). Animals were inoculated with S. pneumoniae (10(8)-10(9) CFU) (n = 14) or saline vehicle (n = 5); in a subset with pneumonia (n = 5), we administered low-dose, inhaled CO gas (100-300 ppm × 60-90 min) at 0, 6, 24, and/or 48 h postinoculation and serially measured blood carboxyhemoglobin (COHb) levels. We found that CO inhalation at 200 ppm for 60 min is well tolerated and achieves a COHb of 6-8% with ambient CO levels ≤ 1 ppm. The COHb level measured at 20 min predicted the 60-min COHb level by the Coburn-Forster-Kane equation with high accuracy. Animals given inhaled CO + antibiotics displayed significantly less ALI at 8 days postinoculation compared with antibiotics alone. Inhaled CO was associated with activation of mitochondrial biogenesis in the lung and with augmentation of renal antioxidative programs. These data support the feasibility of safely delivering inhaled CO gas during mechanical ventilation and provide preliminary evidence that CO may accelerate the resolution of ALI in a clinically relevant nonhuman primate pneumonia model.

Authors
Fredenburgh, LE; Kraft, BD; Hess, DR; Harris, RS; Wolf, MA; Suliman, HB; Roggli, VL; Davies, JD; Winkler, T; Stenzler, A; Baron, RM; Thompson, BT; Choi, AM; Welty-Wolf, KE; Piantadosi, CA
MLA Citation
Fredenburgh, LE, Kraft, BD, Hess, DR, Harris, RS, Wolf, MA, Suliman, HB, Roggli, VL, Davies, JD, Winkler, T, Stenzler, A, Baron, RM, Thompson, BT, Choi, AM, Welty-Wolf, KE, and Piantadosi, CA. "Effects of inhaled CO administration on acute lung injury in baboons with pneumococcal pneumonia." American journal of physiology. Lung cellular and molecular physiology 309.8 (October 2015): L834-L846.
PMID
26320156
Source
epmc
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
309
Issue
8
Publish Date
2015
Start Page
L834
End Page
L846
DOI
10.1152/ajplung.00240.2015

Redox regulation of mitophagy in the lung during murine Staphylococcus aureus sepsis.

Oxidative mitochondrial damage is closely linked to inflammation and cell death, but low levels of reactive oxygen and nitrogen species serve as signals that involve mitochondrial repair and resolution of inflammation. More specifically, cytoprotection relies on the elimination of damaged mitochondria by selective autophagy (mitophagy) during mitochondrial quality control. This aim of this study was to identify and localize mitophagy in the mouse lung as a potentially upregulatable redox response to Staphylococcus aureus sepsis. Fibrin clots loaded with S. aureus (1×10(7) CFU) were implanted abdominally into anesthetized C57BL/6 and B6.129X1-Nfe2l2tm1Ywk/J (Nrf2(-/-)) mice. At the time of implantation, mice were given vancomycin (6mg/kg) and fluid resuscitation. Mouse lungs were harvested at 0, 6, 24, and 48h for bronchoalveolar lavage (BAL), Western blot analysis, and qRT-PCR. To localize mitochondria with autophagy protein LC3, we used lung immunofluorescence staining in LC3-GFP transgenic mice. In C57BL/6 mice, sepsis-induced pulmonary inflammation was detected by significant increases in mRNA for the inflammatory markers IL-1β and TNF-α at 6 and 24h, respectively. BAL cell count and protein also increased. Sepsis suppressed lung Beclin-1 protein, but not mRNA, suggesting activation of canonical autophagy. Notably sepsis also increased the LC3-II autophagosome marker, as well as the lung׳s noncanonical autophagy pathway as evidenced by loss of p62, a redox-regulated scaffolding protein of the autophagosome. In LC3-GFP mouse lungs, immunofluorescence staining showed colocalization of LC3-II to mitochondria, mainly in type 2 epithelium and alveolar macrophages. In contrast, marked accumulation of p62, as well as attenuation of LC3-II in Nrf2-knockout mice supported an overall decrease in autophagic turnover. The downregulation of canonical autophagy during sepsis may contribute to lung inflammation, whereas the switch to noncanonical autophagy selectively removes damaged mitochondria and accompanies tissue repair and cell survival. Furthermore, mitophagy in the alveolar region appears to depend on activation of Nrf2. Thus, efforts to promote mitophagy may be a useful therapeutic adjunct for acute lung injury in sepsis.

Authors
Chang, AL; Ulrich, A; Suliman, HB; Piantadosi, CA
MLA Citation
Chang, AL, Ulrich, A, Suliman, HB, and Piantadosi, CA. "Redox regulation of mitophagy in the lung during murine Staphylococcus aureus sepsis." Free radical biology & medicine 78 (January 2015): 179-189.
PMID
25450328
Source
epmc
Published In
Free Radical Biology & Medicine
Volume
78
Publish Date
2015
Start Page
179
End Page
189
DOI
10.1016/j.freeradbiomed.2014.10.582

Redox mechanisms of cardiomyocyte mitochondrial protection.

Oxidative and nitrosative stress are primary contributors to the loss of myocardial tissue in insults ranging from ischemia/reperfusion injury from coronary artery disease and heart transplantation to sepsis-induced myocardial dysfunction and drug-induced myocardial damage. This cell damage caused by oxidative and nitrosative stress leads to mitochondrial protein, DNA, and lipid modifications, which inhibits energy production and contractile function, potentially leading to cell necrosis and/or apoptosis. However, cardiomyocytes have evolved an elegant set of redox-sensitive mechanisms that respond to and contain oxidative and nitrosative damage. These responses include the rapid induction of antioxidant enzymes, mitochondrial DNA repair mechanisms, selective mitochondrial autophagy (mitophagy), and mitochondrial biogenesis. Coordinated cytoplasmic to nuclear cell-signaling and mitochondrial transcriptional responses to the presence of elevated cytoplasmic oxidant production, e.g., H2O2, allows nuclear translocation of the Nfe2l2 transcription factor and up-regulation of downstream cytoprotective genes such as heme oxygenase-1 which generates physiologic signals, such as CO that up-regulates Nfe212 gene transcription. Simultaneously, a number of other DNA binding transcription factors are expressed and/or activated under redox control, such as Nuclear Respiratory Factor-1 (NRF-1), and lead to the induction of genes involved in both intracellular and mitochondria-specific repair mechanisms. The same insults, particularly those related to vascular stress and inflammation also produce elevated levels of nitric oxide, which also has mitochondrial protein thiol-protective functions and induces mitochondrial biogenesis through cyclic GMP-dependent and perhaps other pathways. This brief review provides an overview of these pathways and interconnected cardiac repair mechanisms.

Authors
Bartz, RR; Suliman, HB; Piantadosi, CA
MLA Citation
Bartz, RR, Suliman, HB, and Piantadosi, CA. "Redox mechanisms of cardiomyocyte mitochondrial protection." Frontiers in physiology 6 (January 2015): 291-. (Review)
Website
http://hdl.handle.net/10161/13589
PMID
26578967
Source
epmc
Published In
Frontiers in Physiology
Volume
6
Publish Date
2015
Start Page
291
DOI
10.3389/fphys.2015.00291

Peroxisome proliferator-activated receptor γ co-activator 1-α as a critical co-activator of the murine hepatic oxidative stress response and mitochondrial biogenesis in Staphylococcus aureus sepsis.

A key transcriptional regulator of cell metabolism, the peroxisome proliferator-activated receptor γ co-activator 1-α (PPARGC-1-α or PGC-1α), also regulates mitochondrial biogenesis, but its role in antioxidant gene regulation is not well understood. Here, we asked whether genetic heterozygosity of PGC-1α modulates gene expression for the mitochondrial antioxidant enzyme SOD-2 during hepatic inflammatory stress. Using Staphylococcus aureus peritonitis in mice, we found significant Sod2 gene induction in WT mice, whereas PGC-1α heterozygotes (PGC-1α(+/-)) failed to augment Sod2 mRNA and protein levels. Impaired Sod2 regulation in PGC-1α(+/-) mice was accompanied by oxidative stress shown by elevated mitochondrial GSSG/GSH and protein carbonyls. In silico analysis of the mouse proximal Sod2 promoter region revealed consensus binding sites for the Nfe2l2 (Nrf2) transcription factor. Chromatin immunoprecipitation demonstrated diminished Nfe2l2 protein binding to the antioxidant response element promoter site proximal to the Sod2 start site in PGC-1α heterozygous mice, implicating PGC-1α in facilitation of Nfe2l2 DNA binding. Nuclear protein co-immunoprecipitation demonstrated an interaction between hepatic Nfe2l2 and PGC-1α in WT mice that was greatly reduced in PGC-1α(+/-) mice. The data indicate that PGC-1α promotes mitochondrial antioxidant enzyme expression through Nfe2l2-mediated SOD-2 expression in sepsis. The presence of this new PGC-1α-dependent signaling axis indicates that PGC-1α opposes mitochondrial oxidative stress by means of selective induction of one or more antioxidant response element-driven genes. By implication, exploitation of this axis could lead to new pharmacological interventions to improve the antioxidant defenses during oxidative stress-induced mitochondrial damage.

Authors
Cherry, AD; Suliman, HB; Bartz, RR; Piantadosi, CA
MLA Citation
Cherry, AD, Suliman, HB, Bartz, RR, and Piantadosi, CA. "Peroxisome proliferator-activated receptor γ co-activator 1-α as a critical co-activator of the murine hepatic oxidative stress response and mitochondrial biogenesis in Staphylococcus aureus sepsis." The Journal of biological chemistry 289.1 (January 2014): 41-52.
PMID
24253037
Source
epmc
Published In
The Journal of biological chemistry
Volume
289
Issue
1
Publish Date
2014
Start Page
41
End Page
52
DOI
10.1074/jbc.m113.512483

Mitochondrial biogenesis: regulation by endogenous gases during inflammation and organ stress.

The influence of mitochondrial dysfunction on pathological states involving inflammatory and/or oxidative stress in tissues that do not show frank cellular apoptosis or necrosis has been rather difficult to unravel, and the literature is replete with contradictory information. Although such discrepancies have many potential causes related to the type of injurious agent, the severity and duration of the injury, and the particular cells and tissues and the functions involved, it is the successful induction of cellular adaptive responses that ultimately governs the resolution of mitochondrial dysfunction and survival of the cell. Much recent attention has been devoted to unraveling the signaling pathways that activate mitochondrial biogenesis and other processes involved in mitochondrial quality control (QC) during inflammatory and oxidative stress with an eye towards the development of novel targets for therapeutic mitigation of the resultant tissue damage. This review provides a brief overview of this emerging field with an emphasis on the role of signaling through the endogenous gases (NO, CO and H2S) and a redox-based approach that brings transparency to key factors that contribute to the resolution of mitochondrial dysfunction and the maintenance of cell vitality. We make the case that targeted stimulation of mitochondrial biogenesis could be a potentially valuable approach for the development of new therapies for the treatment of diseases for which mitochondrial damage is a major consideration.

Authors
Suliman, HB; Piantadosi, CA
MLA Citation
Suliman, HB, and Piantadosi, CA. "Mitochondrial biogenesis: regulation by endogenous gases during inflammation and organ stress." Current pharmaceutical design 20.35 (January 2014): 5653-5662. (Review)
PMID
24606800
Source
epmc
Published In
Current Pharmaceutical Design
Volume
20
Issue
35
Publish Date
2014
Start Page
5653
End Page
5662
DOI
10.2174/1381612820666140306095717

Staphylococcus aureus sepsis induces early renal mitochondrial DNA repair and mitochondrial biogenesis in mice.

Acute kidney injury (AKI) contributes to the high morbidity and mortality of multi-system organ failure in sepsis. However, recovery of renal function after sepsis-induced AKI suggests active repair of energy-producing pathways. Here, we tested the hypothesis in mice that Staphyloccocus aureus sepsis damages mitochondrial DNA (mtDNA) in the kidney and activates mtDNA repair and mitochondrial biogenesis. Sepsis was induced in wild-type C57Bl/6J and Cox-8 Gfp-tagged mitochondrial-reporter mice via intraperitoneal fibrin clots embedded with S. aureus. Kidneys from surviving mice were harvested at time zero (control), 24, or 48 hours after infection and evaluated for renal inflammation, oxidative stress markers, mtDNA content, and mitochondrial biogenesis markers, and OGG1 and UDG mitochondrial DNA repair enzymes. We examined the kidneys of the mitochondrial reporter mice for changes in staining density and distribution. S. aureus sepsis induced sharp amplification of renal Tnf, Il-10, and Ngal mRNAs with decreased renal mtDNA content and increased tubular and glomerular cell death and accumulation of protein carbonyls and 8-OHdG. Subsequently, mtDNA repair and mitochondrial biogenesis was evidenced by elevated OGG1 levels and significant increases in NRF-1, NRF-2, and mtTFA expression. Overall, renal mitochondrial mass, tracked by citrate synthase mRNA and protein, increased in parallel with changes in mitochondrial GFP-fluorescence especially in proximal tubules in the renal cortex and medulla. Sub-lethal S. aureus sepsis thus induces widespread renal mitochondrial damage that triggers the induction of the renal mtDNA repair protein, OGG1, and mitochondrial biogenesis as a conspicuous resolution mechanism after systemic bacterial infection.

Authors
Bartz, RR; Fu, P; Suliman, HB; Crowley, SD; MacGarvey, NC; Welty-Wolf, K; Piantadosi, CA
MLA Citation
Bartz, RR, Fu, P, Suliman, HB, Crowley, SD, MacGarvey, NC, Welty-Wolf, K, and Piantadosi, CA. "Staphylococcus aureus sepsis induces early renal mitochondrial DNA repair and mitochondrial biogenesis in mice." PloS one 9.7 (January 2014): e100912-.
PMID
24988481
Source
epmc
Published In
PloS one
Volume
9
Issue
7
Publish Date
2014
Start Page
e100912
DOI
10.1371/journal.pone.0100912

Redox regulation of mitochondrial biogenesis.

The cell renews, adapts, or expands its mitochondrial population during episodes of cell damage or periods of intensified energy demand by the induction of mitochondrial biogenesis. This bigenomic program is modulated by redox-sensitive signals that respond to physiological nitric oxide (NO), carbon monoxide (CO), and mitochondrial reactive oxygen species production. This review summarizes our current ideas about the pathways involved in the activation of mitochondrial biogenesis by the physiological gases leading to changes in the redox milieu of the cell, with an emphasis on the responses to oxidative stress and inflammation. The cell's energy supply is protected from conditions that damage mitochondria by an inducible transcriptional program of mitochondrial biogenesis that operates in large part through redox signals involving the nitric oxide synthase and the heme oxygenase-1/CO systems. These redox events stimulate the coordinated activities of several multifunctional transcription factors and coactivators also involved in the elimination of defective mitochondria and the expression of counterinflammatory and antioxidant genes, such as IL10 and SOD2, as part of a unified damage-control network. The redox-regulated mechanisms of mitochondrial biogenesis schematically outlined in the graphical abstract link mitochondrial quality control to an enhanced capacity to support the cell's metabolic needs while improving its resistance to metabolic failure and avoidance of cell death during periods of oxidative stress.

Authors
Piantadosi, CA; Suliman, HB
MLA Citation
Piantadosi, CA, and Suliman, HB. "Redox regulation of mitochondrial biogenesis." Free Radic Biol Med 53.11 (December 1, 2012): 2043-2053. (Review)
PMID
23000245
Source
pubmed
Published In
Free Radical Biology and Medicine
Volume
53
Issue
11
Publish Date
2012
Start Page
2043
End Page
2053
DOI
10.1016/j.freeradbiomed.2012.09.014

Hedgehog controls hepatic stellate cell fate by regulating metabolism.

BACKGROUND & AIMS: The pathogenesis of cirrhosis, a disabling outcome of defective liver repair, involves deregulated accumulation of myofibroblasts derived from quiescent hepatic stellate cells (HSCs), but the mechanisms that control transdifferentiation of HSCs are poorly understood. We investigated whether the Hedgehog (Hh) pathway controls the fate of HSCs by regulating metabolism. METHODS: Microarray, quantitative polymerase chain reaction, and immunoblot analyses were used to identify metabolic genes that were differentially expressed in quiescent vs myofibroblast HSCs. Glycolysis and lactate production were disrupted in HSCs to determine if metabolism influenced transdifferentiation. Hh signaling and hypoxia-inducible factor 1α (HIF1α) activity were altered to identify factors that alter glycolytic activity. Changes in expression of genes that regulate glycolysis were quantified and localized in biopsy samples from patients with cirrhosis and liver samples from mice following administration of CCl(4) or bile duct ligation. Mice were given systemic inhibitors of Hh to determine if they affect glycolytic activity of the hepatic stroma; Hh signaling was also conditionally disrupted in myofibroblasts to determine the effects of glycolytic activity. RESULTS: Transdifferentiation of cultured, quiescent HSCs into myofibroblasts induced glycolysis and caused lactate accumulation. Increased expression of genes that regulate glycolysis required Hh signaling and involved induction of HIF1α. Inhibitors of Hh signaling, HIF1α, glycolysis, or lactate accumulation converted myofibroblasts to quiescent HSCs. In diseased livers of animals and patients, numbers of glycolytic stromal cells were associated with the severity of fibrosis. Conditional disruption of Hh signaling in myofibroblasts reduced numbers of glycolytic myofibroblasts and liver fibrosis in mice; similar effects were observed following administration of pharmacologic inhibitors of Hh. CONCLUSIONS: Hedgehog signaling controls the fate of HSCs by regulating metabolism. These findings might be applied to diagnosis and treatment of patients with cirrhosis.

Authors
Chen, Y; Choi, SS; Michelotti, GA; Chan, IS; Swiderska-Syn, M; Karaca, GF; Xie, G; Moylan, CA; Garibaldi, F; Premont, R; Suliman, HB; Piantadosi, CA; Diehl, AM
MLA Citation
Chen, Y, Choi, SS, Michelotti, GA, Chan, IS, Swiderska-Syn, M, Karaca, GF, Xie, G, Moylan, CA, Garibaldi, F, Premont, R, Suliman, HB, Piantadosi, CA, and Diehl, AM. "Hedgehog controls hepatic stellate cell fate by regulating metabolism." Gastroenterology 143.5 (November 2012): 1319-29.e1-11-.
PMID
22885334
Source
pubmed
Published In
Gastroenterology
Volume
143
Issue
5
Publish Date
2012
Start Page
1319-29.e1-11
DOI
10.1053/j.gastro.2012.07.115

Nrf2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in Staphylococcus aureus pneumonia in mice.

Acute lung injury (ALI) initiates protective responses involving genes downstream of the Nrf2 (Nfe2l2) transcription factor, including heme oxygenase-1 (HO-1), which stimulates mitochondrial biogenesis and related anti-inflammatory processes. We examined mitochondrial biogenesis during Staphylococcus aureus pneumonia in mice and the effect of Nrf2 deficiency on lung mitochondrial biogenesis and resolution of lung inflammation. S. aureus pneumonia established by nasal insufflation of live bacteria was studied in mitochondrial reporter (mt-COX8-GFP) mice, wild-type (WT) mice, and Nrf2⁻/⁻ mice. Bronchoalveolar lavage, wet/dry ratios, real-time RT-PCR and Western analysis, immunohistochemistry, and fluorescence microscopy were performed on the lung at 0, 6, 24, and 48 h. The mice survived S. aureus inoculations at 5×10⁸ CFU despite diffuse lung inflammation and edema, but the Nrf2⁻/⁻ lung showed increased ALI. In mt-COX8-GFP mice, mitochondrial fluorescence was enhanced in bronchial and alveolar type II (AT2) epithelial cells. WT mice displayed rapid HO-1 upregulation and lower proinflammatory TNF-α, IL-1β, and CCL2 and, especially in AT2 cells, higher anti-inflammatory IL-10 and suppressor of cytokine signaling-3 than Nrf2⁻/⁻ mice. In the alveolar region, WT but not Nrf2⁻/⁻ mice showed strongly induced nuclear respiratory factor-1, PGC-1α, mitochondrial transcription factor-A, SOD2, Bnip3, mtDNA copy number, and citrate synthase. These findings indicate that S. aureus pneumonia induces Nrf2-dependent mitochondrial biogenesis in the alveolar region, mainly in AT2 cells. Absence of Nrf2 suppresses the alveolar transcriptional network for mitochondrial biogenesis and anti-inflammation, which worsens ALI. The findings link redox activation of mitochondrial biogenesis to ALI resolution.

Authors
Athale, J; Ulrich, A; MacGarvey, NC; Bartz, RR; Welty-Wolf, KE; Suliman, HB; Piantadosi, CA
MLA Citation
Athale, J, Ulrich, A, MacGarvey, NC, Bartz, RR, Welty-Wolf, KE, Suliman, HB, and Piantadosi, CA. "Nrf2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in Staphylococcus aureus pneumonia in mice." Free Radic Biol Med 53.8 (October 15, 2012): 1584-1594.
PMID
22940620
Source
pubmed
Published In
Free Radical Biology and Medicine
Volume
53
Issue
8
Publish Date
2012
Start Page
1584
End Page
1594
DOI
10.1016/j.freeradbiomed.2012.08.009

What is the role of hyperbaric oxygen in the management of bisphosphonate-related osteonecrosis of the jaw: a randomized controlled trial of hyperbaric oxygen as an adjunct to surgery and antibiotics.

PURPOSE: This study tested hyperbaric oxygen (HBO) as an adjunct to surgery and antibiotics in the treatment of bisphosphonate-related osteonecrosis of the jaw (ONJ) and evaluated its effects on gingival healing, pain, and quality of life. MATERIALS AND METHODS: The investigators implemented a randomized controlled trial and enrolled a sample composed of patients with ONJ, where the predictor variable was HBO administered at 2 atm twice a day for 40 treatments as an adjunct to conventional therapy of surgery and antibiotics versus conventional therapy alone. Over the next 24 months, oral lesion size and number, pain, and quality of life were assessed. RESULTS: Forty-six patients (mean age, 66 yrs; 57% women) contributed data to the trial. There were no statistically significant differences in the distribution of variables used to assess randomization success between the HBO and standard treatment groups. Seventeen of 25 HBO-treated patients (68%) improved versus 8 of 21 controls (38.1%; P = .043, χ(2) test). Mean time to improvement was 39.7 weeks (95% confidence interval [CI], 22.4 to 57.0 weeks) for HBO-treated patients versus 67.9 weeks (95 CI, 48.4 to 87.5 weeks) for controls (P = .03, log-rank test). However, complete gingival healing occurred in only 14 of 25 HBO-treated patients (52%) versus 7 of 21 controls (33.3%; P = .203, χ(2) test), and time to healing was 59 weeks (95% CI, 42.8% to 75.8%) for HBO-treated patients versus 70 weeks (95 CI, 52.2% to 88.36%) for controls (P = .32, log-rank test). Pain decreased faster for HBO-treated subjects (P < .01, linear regression). Quality-of-life scores for physical health (P = .002) and perceived health (P = .043) decreased at 6 months for control group but for not the HBO group. CONCLUSIONS: ONJ is multifactorial and no single treatment modality is likely to reverse it; however, it is treatable and even advanced presentations can improve with intensive multimodal therapy. Clinically, HBO appears to be a useful adjunct to ONJ treatment, particularly for more severe cases, although this study was underpowered to fully support this claim.

Authors
Freiberger, JJ; Padilla-Burgos, R; McGraw, T; Suliman, HB; Kraft, KH; Stolp, BW; Moon, RE; Piantadosi, CA
MLA Citation
Freiberger, JJ, Padilla-Burgos, R, McGraw, T, Suliman, HB, Kraft, KH, Stolp, BW, Moon, RE, and Piantadosi, CA. "What is the role of hyperbaric oxygen in the management of bisphosphonate-related osteonecrosis of the jaw: a randomized controlled trial of hyperbaric oxygen as an adjunct to surgery and antibiotics." J Oral Maxillofac Surg 70.7 (July 2012): 1573-1583.
PMID
22698292
Source
pubmed
Published In
Journal of Oral and Maxillofacial Surgery
Volume
70
Issue
7
Publish Date
2012
Start Page
1573
End Page
1583
DOI
10.1016/j.joms.2012.04.001

Activation of mitochondrial biogenesis by heme oxygenase-1-mediated NF-E2-related factor-2 induction rescues mice from lethal Staphylococcus aureus sepsis.

RATIONALE: Mitochondrial damage is an important component of multiple organ failure syndrome, a highly lethal complication of severe sepsis that lacks specific therapy. Mitochondrial quality control is regulated in part by the heme oxygenase-1 (HO-1; Hmox1) system through the redox-regulated NF-E2-related factor-2 (Nrf2) transcription factor, but its role in mitochondrial biogenesis in Staphylococcus aureus sepsis is unknown. OBJECTIVES: To test the hypothesis that Nrf2-dependent up-regulation of the HO-1/carbon monoxide (CO) system would preserve mitochondrial biogenesis and rescue mice from lethal S. aureus sepsis. METHODS: A controlled murine S. aureus peritonitis model with and without inhaled CO was examined for HO-1 and Nrf2 regulation of mitochondrial biogenesis and the resolution of hepatic mitochondrial damage. MEASUREMENTS AND MAIN RESULTS: Sepsis survival was significantly enhanced using inhaled CO (250 ppm once-daily for 1 h), and linked mechanistically to Hmox1 induction and mitochondrial HO activity through Nrf2 transcriptional and Akt kinase activity. HO-1/CO stimulated Nrf2-dependent gene expression and nuclear accumulation of nuclear respiratory factor-1, -2α (Gabpa), and peroxisome proliferator-activated receptor gamma coactivator-1α; increased mitochondrial transcription factor-A and citrate synthase protein levels; and augmented mtDNA copy number. CO enhanced antiinflammatory IL-10 and reduced proinflammatory tumor necrosis factor-α production. By contrast, Nrf2(-/-) and Akt1(-/-) mice lacked CO induction of Hmox1 and mitochondrial biogenesis, and CO rescued neither strain from S. aureus sepsis. CONCLUSIONS: We identify an inducible Nrf2/HO-1 regulatory cycle for mitochondrial biogenesis that is prosurvival and counter-inflammatory in sepsis, and describe targeted induction of mitochondrial biogenesis as a potential multiple organ failure therapy.

Authors
MacGarvey, NC; Suliman, HB; Bartz, RR; Fu, P; Withers, CM; Welty-Wolf, KE; Piantadosi, CA
MLA Citation
MacGarvey, NC, Suliman, HB, Bartz, RR, Fu, P, Withers, CM, Welty-Wolf, KE, and Piantadosi, CA. "Activation of mitochondrial biogenesis by heme oxygenase-1-mediated NF-E2-related factor-2 induction rescues mice from lethal Staphylococcus aureus sepsis." Am J Respir Crit Care Med 185.8 (April 15, 2012): 851-861.
PMID
22312014
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
185
Issue
8
Publish Date
2012
Start Page
851
End Page
861
DOI
10.1164/rccm.201106-1152OC

Transcriptional control of mitochondrial biogenesis and its interface with inflammatory processes.

BACKGROUND: Cells avoid major mitochondrial damage and energy failure during systemic inflammatory states, such as severe acute infections, by specific targeting of the inflammatory response and by inducing anti-inflammatory and anti-oxidant defenses. Recent evidence indicates that these cell defenses also include mitochondrial biogenesis and the clearance of damaged mitochondria through autophagy. SCOPE OF REVIEW: This review addresses a group of transcriptional signaling mechanisms that engage mitochondrial biogenesis, including energy-sensing and redox-regulated transcription factors and co-activators, after major inflammatory events. MAJOR CONCLUSIONS: Stimulation of the innate immune system by activation of toll-like receptors (TLR) generates pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α)and interleukin-1β (IL-1β), necessary for optimal host defense, but which also contribute to mitochondrial damage through oxidative stress and other mechanisms. To protect its energy supply, host cells sense mitochondrial damage and initiate mitochondrial biogenesis under the control of an inducible transcriptional program that also activates anti-oxidant and anti-inflammatory gene expression. This multifunctional network not only increases cellular resistance to metabolic failure, oxidative stress, and cell death, but promotes immune tolerance as shown in the graphical abstract. GENERAL SIGNIFICANCE: The post-inflammatory induction of mitochondrial biogenesis supports metabolic function and cell viability while helping to control inflammation. In clinical settings, patients recovering from severe systemic infections may develop transient immune suppression, placing them at risk for recurrent infection, but there may be therapeutic opportunities to enhance mitochondrial quality control that would improve the resolution of life-threatening host responses to such infections.

Authors
Piantadosi, CA; Suliman, HB
MLA Citation
Piantadosi, CA, and Suliman, HB. "Transcriptional control of mitochondrial biogenesis and its interface with inflammatory processes." Biochim Biophys Acta 1820.4 (April 2012): 532-541. (Review)
PMID
22265687
Source
pubmed
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
1820
Issue
4
Publish Date
2012
Start Page
532
End Page
541
DOI
10.1016/j.bbagen.2012.01.003

PGC-1 alpha and the Mitochondrial Antioxidant Response during Sepsis

Authors
Cherry, AD; Bartz, RR; Fu, P; Piantadosi, CA; Suliman, HB
MLA Citation
Cherry, AD, Bartz, RR, Fu, P, Piantadosi, CA, and Suliman, HB. "PGC-1 alpha and the Mitochondrial Antioxidant Response during Sepsis." November 1, 2011.
Source
wos-lite
Published In
Free Radical Biology & Medicine
Volume
51
Publish Date
2011
Start Page
S12
End Page
S13
DOI
10.1016/j.freeradbiomed.2011.10.026

Heme Oxygenase 1 Promotes Murine Stem Cell Differentiation into Beating Cardiomyocytes

Authors
Suliman, HB; Piantadosi, CA
MLA Citation
Suliman, HB, and Piantadosi, CA. "Heme Oxygenase 1 Promotes Murine Stem Cell Differentiation into Beating Cardiomyocytes." November 1, 2011.
Source
wos-lite
Published In
Free Radical Biology & Medicine
Volume
51
Publish Date
2011
Start Page
S51
End Page
S51
DOI
10.1016/j.freeradbiomed.2011.10.131

Heme oxygenase-1 couples activation of mitochondrial biogenesis to anti-inflammatory cytokine expression.

The induction of heme oxygenase-1 (HO-1; Hmox1) by inflammation, for instance in sepsis, is associated both with an anti-inflammatory response and with mitochondrial biogenesis. Here, we tested the idea that HO-1, acting through the Nfe2l2 (Nrf2) transcription factor, links anti-inflammatory cytokine expression to activation of mitochondrial biogenesis. HO-1 induction after LPS stimulated anti-inflammatory IL-10 and IL-1 receptor antagonist (IL-1Ra) expression in mouse liver, human HepG2 cells, and mouse J774.1 macrophages but blunted tumor necrosis factor-α expression. This was accompanied by nuclear Nfe2l2 accumulation and led us to identify abundant Nfe2l2 and other mitochondrial biogenesis transcription factor binding sites in the promoter regions of IL10 and IL1Ra compared with pro-inflammatory genes regulated by NF-κΒ. Mechanistically, HO-1, through its CO product, enabled these transcription factors to bind the core IL10 and IL1Ra promoters, which for IL10 included Nfe2l2, nuclear respiratory factor (NRF)-2 (Gabpa), and MEF2, and for IL1Ra, included NRF-1 and MEF2. In cells, Hmox1 or Nfe2l2 RNA silencing prevented IL-10 and IL-1Ra up-regulation, and HO-1 induction failed post-LPS in Nfe2l2-silenced cells and post-sepsis in Nfe2l2(-/-) mice. Nfe2l2(-/-) mice compared with WT mice, showed more liver damage, higher mortality, and ineffective CO rescue in sepsis. Nfe2l2(-/-) mice in sepsis also generated higher hepatic TNF-α mRNA levels, lower NRF-1 and PGC-1α mRNA levels, and no enhancement of anti-inflammatory Il10, Socs3, or bcl-x(L) gene expression. These findings disclose a highly structured transcriptional network that couples mitochondrial biogenesis to counter-inflammation with major implications for immune suppression in sepsis.

Authors
Piantadosi, CA; Withers, CM; Bartz, RR; MacGarvey, NC; Fu, P; Sweeney, TE; Welty-Wolf, KE; Suliman, HB
MLA Citation
Piantadosi, CA, Withers, CM, Bartz, RR, MacGarvey, NC, Fu, P, Sweeney, TE, Welty-Wolf, KE, and Suliman, HB. "Heme oxygenase-1 couples activation of mitochondrial biogenesis to anti-inflammatory cytokine expression." J Biol Chem 286.18 (May 6, 2011): 16374-16385.
PMID
21454555
Source
pubmed
Published In
The Journal of biological chemistry
Volume
286
Issue
18
Publish Date
2011
Start Page
16374
End Page
16385
DOI
10.1074/jbc.M110.207738

Redox Activation of Mitochondrial Biogenesis by Heme Oxygenase-1 Exerts Counter-regulatory Control over NF-kB-dependent Cytokine Production

Authors
Piantadosi, CA; Withers, CM; Bartz, RR; MacGarvey, NC; Sweeney, TE; Welty-Wolf, KE; Suliman, HB
MLA Citation
Piantadosi, CA, Withers, CM, Bartz, RR, MacGarvey, NC, Sweeney, TE, Welty-Wolf, KE, and Suliman, HB. "Redox Activation of Mitochondrial Biogenesis by Heme Oxygenase-1 Exerts Counter-regulatory Control over NF-kB-dependent Cytokine Production." April 2011.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
25
Publish Date
2011

Staphylococcus aureus sepsis and mitochondrial accrual of the 8-oxoguanine DNA glycosylase DNA repair enzyme in mice.

RATIONALE: Damage to mitochondrial DNA (mtDNA) by the production of reactive oxygen species during inflammatory states, such as sepsis, is repaired by poorly understood mechanisms. OBJECTIVES: To test the hypothesis that the DNA repair enzyme, 8-oxoguanine DNA glycosylase (OGG1), contributes to mtDNA repair in sepsis. METHODS: Using a well-characterized mouse model of Staphylococcus aureus sepsis, we analyzed molecular markers for mitochondrial biogenesis and OGG1 translocation into liver mitochondria as well as OGG1 mRNA expression at 0, 24, 48, and 72 hours after infection. The effects of OGG1 RNA silencing on mtDNA content were determined in control, tumor necrosis factor-α, and peptidoglycan-exposed rat hepatoma cells. Based on in situ analysis of the OGG1 promoter region, chromatin immunoprecipitation assays were performed for nuclear respiratory factor (NRF)-1 and NRF-2α GA-binding protein (GABP) binding to the promoter of OGG1. MEASUREMENTS AND MAIN RESULTS: Mice infected with 10(7) cfu S. aureus intraperitoneally demonstrated hepatic oxidative mtDNA damage and significantly lower hepatic mtDNA content as well as increased mitochondrial OGG1 protein and enzyme activity compared with control mice. The infection also caused increases in hepatic OGG1 transcript levels and NRF-1 and NRF-2α transcript and protein levels. A bioinformatics analysis of the Ogg1 gene locus identified several promoter sites containing NRF-1 and NRF-2α DNA binding motifs, and chromatin immunoprecipitation assays confirmed in situ binding of both transcription factors to the Ogg1 promoter within 24 hours of infection. CONCLUSIONS: These studies identify OGG1 as an early mitochondrial response protein during sepsis under regulation by the NRF-1 and NRF-2α transcription factors that regulate mitochondrial biogenesis.

Authors
Bartz, RR; Suliman, HB; Fu, P; Welty-Wolf, K; Carraway, MS; MacGarvey, NC; Withers, CM; Sweeney, TE; Piantadosi, CA
MLA Citation
Bartz, RR, Suliman, HB, Fu, P, Welty-Wolf, K, Carraway, MS, MacGarvey, NC, Withers, CM, Sweeney, TE, and Piantadosi, CA. "Staphylococcus aureus sepsis and mitochondrial accrual of the 8-oxoguanine DNA glycosylase DNA repair enzyme in mice." Am J Respir Crit Care Med 183.2 (January 15, 2011): 226-233.
PMID
20732986
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
183
Issue
2
Publish Date
2011
Start Page
226
End Page
233
DOI
10.1164/rccm.200911-1709OC

A toll-like receptor 2 pathway regulates the Ppargc1a/b metabolic co-activators in mice with Staphylococcal aureus sepsis.

Activation of the host antibacterial defenses by the toll-like receptors (TLR) also selectively activates energy-sensing and metabolic pathways, but the mechanisms are poorly understood. This includes the metabolic and mitochondrial biogenesis master co-activators, Ppargc1a (PGC-1α) and Ppargc1b (PGC-1β) in Staphylococcus aureus (S. aureus) sepsis. The expression of these genes in the liver is markedly attenuated inTLR2(-/-) mice and markedly accentuated in TLR4(-/-) mice compared with wild type (WT) mice. We sought to explain this difference by using specific TLR-pathway knockout mice to test the hypothesis that these co-activator genes are directly regulated through TLR2 signaling. By comparing their responses to S. aureus with WT mice, we found that MyD88-deficient and MAL-deficient mice expressed hepatic Ppargc1a and Ppargc1b normally, but that neither gene was activated in TRAM-deficient mice. Ppargc1a/b activation did not require NF-kβ, but did require an interferon response factor (IRF), because neither gene was activated in IRF-3/7 double-knockout mice in sepsis, but both were activated normally in Unc93b1-deficient (3d) mice. Nuclear IRF-7 levels in TLR2(-/-) and TLR4(-/-) mice decreased and increased respectively post-inoculation and IRF-7 DNA-binding at the Ppargc1a promoter was demonstrated by chromatin immunoprecipitation. Also, a TLR2-TLR4-TRAM native hepatic protein complex was detected by immunoprecipitation within 6 h of S. aureus inoculation that could support MyD88-independent signaling to Ppargc1a/b. Overall, these findings disclose a novel MyD88-independent pathway in S. aureus sepsis that links TLR2 and TLR4 signaling in innate immunity to Ppargc1a/b gene regulation in a critical metabolic organ, the liver, by means of TRAM, TRIF, and IRF-7.

Authors
Sweeney, TE; Suliman, HB; Hollingsworth, JW; Welty-Wolf, KE; Piantadosi, CA
MLA Citation
Sweeney, TE, Suliman, HB, Hollingsworth, JW, Welty-Wolf, KE, and Piantadosi, CA. "A toll-like receptor 2 pathway regulates the Ppargc1a/b metabolic co-activators in mice with Staphylococcal aureus sepsis." PLoS One 6.9 (2011): e25249-.
PMID
21966468
Source
pubmed
Published In
PloS one
Volume
6
Issue
9
Publish Date
2011
Start Page
e25249
DOI
10.1371/journal.pone.0025249

Survival in critical illness is associated with early activation of mitochondrial biogenesis.

RATIONALE: We previously reported outcome-associated decreases in muscle energetic status and mitochondrial dysfunction in septic patients with multiorgan failure. We postulate that survivors have a greater ability to maintain or recover normal mitochondrial functionality. OBJECTIVES: To determine whether mitochondrial biogenesis, the process promoting mitochondrial capacity, is affected in critically ill patients. METHODS: Muscle biopsies were taken from 16 critically ill patients recently admitted to intensive care (average 1-2 d) and from 10 healthy, age-matched patients undergoing elective hip surgery. MEASUREMENTS AND MAIN RESULTS: Survival, mitochondrial morphology, mitochondrial protein content and enzyme activity, mitochondrial biogenesis factor mRNA, microarray analysis, and phosphorylated (energy) metabolites were determined. Ten of 16 critically ill patients survived intensive care. Mitochondrial size increased with worsening outcome, suggestive of swelling. Respiratory protein subunits and transcripts were depleted in critically ill patients and to a greater extent in nonsurvivors. The mRNA content of peroxisome proliferator-activated receptor γ coactivator 1-α (transcriptional coactivator of mitochondrial biogenesis) was only elevated in survivors, as was the mitochondrial oxidative stress protein manganese superoxide dismutase. Eventual survivors demonstrated elevated muscle ATP and a decreased phosphocreatine/ATP ratio. CONCLUSIONS: Eventual survivors responded early to critical illness with mitochondrial biogenesis and antioxidant defense responses. These responses may partially counteract mitochondrial protein depletion, helping to maintain functionality and energetic status. Impaired responses, as suggested in nonsurvivors, could increase susceptibility to mitochondrial damage and cellular energetic failure or impede the ability to recover normal function. Clinical trial registered with clinical trials.gov (NCT00187824).

Authors
Carré, JE; Orban, J-C; Re, L; Felsmann, K; Iffert, W; Bauer, M; Suliman, HB; Piantadosi, CA; Mayhew, TM; Breen, P; Stotz, M; Singer, M
MLA Citation
Carré, JE, Orban, J-C, Re, L, Felsmann, K, Iffert, W, Bauer, M, Suliman, HB, Piantadosi, CA, Mayhew, TM, Breen, P, Stotz, M, and Singer, M. "Survival in critical illness is associated with early activation of mitochondrial biogenesis." Am J Respir Crit Care Med 182.6 (September 15, 2010): 745-751.
PMID
20538956
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
182
Issue
6
Publish Date
2010
Start Page
745
End Page
751
DOI
10.1164/rccm.201003-0326OC

Co-regulation of nuclear respiratory factor-1 by NFkappaB and CREB links LPS-induced inflammation to mitochondrial biogenesis.

The nuclear respiratory factor-1 (NRF1) gene is activated by lipopolysaccharide (LPS), which might reflect TLR4-mediated mitigation of cellular inflammatory damage via initiation of mitochondrial biogenesis. To test this hypothesis, we examined NRF1 promoter regulation by NFκB, and identified interspecies-conserved κB-responsive promoter and intronic elements in the NRF1 locus. In mice, activation of Nrf1 and its downstream target, Tfam, by Escherichia coli was contingent on NFκB, and in LPS-treated hepatocytes, NFκB served as an NRF1 enhancer element in conjunction with NFκB promoter binding. Unexpectedly, optimal NRF1 promoter activity after LPS also required binding by the energy-state-dependent transcription factor CREB. EMSA and ChIP assays confirmed p65 and CREB binding to the NRF1 promoter and p65 binding to intron 1. Functionality for both transcription factors was validated by gene-knockdown studies. LPS regulation of NRF1 led to mtDNA-encoded gene expression and expansion of mtDNA copy number. In cells expressing plasmid constructs containing the NRF-1 promoter and GFP, LPS-dependent reporter activity was abolished by cis-acting κB-element mutations, and nuclear accumulation of NFκB and CREB demonstrated dependence on mitochondrial H(2)O(2). These findings indicate that TLR4-dependent NFκB and CREB activation co-regulate the NRF1 promoter with NFκB intronic enhancement and redox-regulated nuclear translocation, leading to downstream target-gene expression, and identify NRF-1 as an early-phase component of the host antibacterial defenses.

Authors
Suliman, HB; Sweeney, TE; Withers, CM; Piantadosi, CA
MLA Citation
Suliman, HB, Sweeney, TE, Withers, CM, and Piantadosi, CA. "Co-regulation of nuclear respiratory factor-1 by NFkappaB and CREB links LPS-induced inflammation to mitochondrial biogenesis." J Cell Sci 123.Pt 15 (August 1, 2010): 2565-2575.
Website
http://hdl.handle.net/10161/4185
PMID
20587593
Source
pubmed
Published In
Journal of cell science
Volume
123
Issue
Pt 15
Publish Date
2010
Start Page
2565
End Page
2575
DOI
10.1242/jcs.064089

Differential regulation of the PGC family of genes in a mouse model of Staphylococcus aureus sepsis.

The PGC family of transcriptional co-activators (PGC-1alpha [Ppargc1a], PGC-1beta [Ppargc1b], and PRC [Pprc]) coordinates the upregulation of mitochondrial biogenesis, and Ppargc1a is known to be activated in response to mitochondrial damage in sepsis. Therefore, we postulated that the PGC family is regulated by the innate immune system. We investigated whether mitochondrial biogenesis and PGC gene expression are disrupted in an established model of Staphylococcus aureus sepsis both in mice with impaired innate immune function (TLR2-/- and TLR4-/-) and in wild-type controls. We found an early up-regulation of Ppargc1a and Ppargc1b post-infection (at 6 h) in WT mice, but the expression of both genes was concordantly dysregulated in TLR2-/- mice (no increase at 6 h) and in TLR4-/- mice (amplified at 6 h). However, the third family member, PRC, was regulated differently, and its expression increased significantly at 24 h in all three mouse strains (WT, TLR2-/-, and TLR4-/-). In silico analyses showed that Ppargc1a and Ppargc1b share binding sites for microRNA mmu-mir-202-3p. Thus, miRNA-mediated post-transcriptional mRNA degradation could account for the failure to increase the expression of both genes in TLR2-/- mice. The expression of mmu-mir-202-3p was measured by real-time PCR and found to be significantly increased in TLR2-/- but not in WT or TLR4-/- mice. In addition, it was found that mir-202-3p functionally decreases Ppargc1a mRNA in vitro. Thus, both innate immune signaling through the TLRs and mir-202-3p-mediated mRNA degradation are implicated in the co-regulation of Ppargc1a and Ppargc1b during inflammation. Moreover, the identification of mir-202-3p as a potential factor for Ppargc1a and Ppargc1b repression in acute inflammation may open new avenues for mitochondrial research and, potentially, therapy.

Authors
Sweeney, TE; Suliman, HB; Hollingsworth, JW; Piantadosi, CA
MLA Citation
Sweeney, TE, Suliman, HB, Hollingsworth, JW, and Piantadosi, CA. "Differential regulation of the PGC family of genes in a mouse model of Staphylococcus aureus sepsis. (Published online)" PLoS One 5.7 (July 15, 2010): e11606-.
PMID
20657826
Source
pubmed
Published In
PloS one
Volume
5
Issue
7
Publish Date
2010
Start Page
e11606
DOI
10.1371/journal.pone.0011606

Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart.

RATIONALE: Erythropoietin (EPO) is often administered to cardiac patients with anemia, particularly from chronic kidney disease, and stimulation of erythropoiesis may stabilize left ventricular and renal function by recruiting protective effects beyond the correction of anemia. OBJECTIVE: We examined the hypothesis that EPO receptor (EpoR) ligand-binding, which activates endothelial NO synthase (eNOS), regulates the prosurvival program of mitochondrial biogenesis in the heart. METHODS AND RESULTS: We investigated the effects of EPO on mitochondrial biogenesis over 14 days in healthy mice. Mice expressing a mitochondrial green fluorescent protein reporter construct demonstrated sharp increases in myocardial mitochondrial density after 3 days of EPO administration that peaked at 7 days and surpassed hepatic or renal effects and anteceded significant increases in blood hemoglobin content. Quantitatively, in wild-type mice, complex II activity, state 3 respiration, and mtDNA copy number increased significantly; also, resting energy expenditure and natural running speed improved, with no evidence of an increase in left ventricular mass index. Mechanistically, EPO activated cardiac mitochondrial biogenesis by enhancement of nuclear respiratory factor-1, PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator 1alpha), and mitochondrial transcription factor-A gene expression in wild-type but not in eNOS(-/-) or protein kinase B (Akt1)(-/-) mice. EpoR was required, because EpoR silencing in cardiomyocytes blocked EPO-mediated nuclear translocation of nuclear respiratory factor-1. CONCLUSIONS: These findings support a new physiological and protective role for EPO, acting through its cell surface receptor and eNOS-Akt1 signal transduction, in matching cardiac mitochondrial mass to the convective O(2) transport capacity as erythrocyte mass expands.

Authors
Carraway, MS; Suliman, HB; Jones, WS; Chen, C-W; Babiker, A; Piantadosi, CA
MLA Citation
Carraway, MS, Suliman, HB, Jones, WS, Chen, C-W, Babiker, A, and Piantadosi, CA. "Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart." Circ Res 106.11 (June 11, 2010): 1722-1730.
PMID
20395592
Source
pubmed
Published In
Circulation Research
Volume
106
Issue
11
Publish Date
2010
Start Page
1722
End Page
1730
DOI
10.1161/CIRCRESAHA.109.214353

Nitric oxide synthase-2 regulates mitochondrial Hsp60 chaperone function during bacterial peritonitis in mice.

Nitric oxide synthase-2 (NOS2) plays a critical role in reactive nitrogen species generation and cysteine modifications that influence mitochondrial function and signaling during inflammation. Here, we investigated the role of NOS2 in hepatic mitochondrial biogenesis during Escherichia coli peritonitis in mice. NOS2(-/-) mice displayed smaller mitochondrial biogenesis responses than Wt mice during E. coli infection according to differences in mRNA levels for the PGC-1 alpha coactivator, nuclear respiratory factor-1, mitochondrial transcription factor-A (Tfam), and mtDNA polymerase (Pol gamma). NOS2(-/-) mice did not significantly increase mitochondrial Tfam and Pol gamma protein levels during infection in conjunction with impaired mitochondrial DNA (mtDNA) transcription, loss of mtDNA copy number, and lower State 3 respiration rates. NOS2 blockade in mitochondrial-GFP reporter mice disrupted Hsp60 localization to mitochondria after E. coli exposure. Mechanistically, biotin-switch and immunoprecipitation studies demonstrated NOS2 binding to and S-nitros(yl)ation of Hsp60 and Hsp70. Specifically, NOS2 promoted Tfam accumulation in mitochondria by regulation of Hsp60-Tfam binding via S-nitros(yl)ation. In hepatocytes, site-directed mutagenesis identified (237)Cys as a critical residue for Hsp60 S-nitros(yl)ation. Thus, the role of NOS2 in inflammation-induced mitochondrial biogenesis involves both optimal gene expression for nuclear-encoded mtDNA-binding proteins and functional regulation of the Hsp60 chaperone that enables their importation for mtDNA transcription and replication.

Authors
Suliman, HB; Babiker, A; Withers, CM; Sweeney, TE; Carraway, MS; Tatro, LG; Bartz, RR; Welty-Wolf, KE; Piantadosi, CA
MLA Citation
Suliman, HB, Babiker, A, Withers, CM, Sweeney, TE, Carraway, MS, Tatro, LG, Bartz, RR, Welty-Wolf, KE, and Piantadosi, CA. "Nitric oxide synthase-2 regulates mitochondrial Hsp60 chaperone function during bacterial peritonitis in mice." Free Radic Biol Med 48.5 (March 1, 2010): 736-746.
PMID
20043987
Source
pubmed
Published In
Free Radical Biology and Medicine
Volume
48
Issue
5
Publish Date
2010
Start Page
736
End Page
746
DOI
10.1016/j.freeradbiomed.2009.12.019

Deconstructing Mitochondria: Co-localization of HO-1 and LC3II Mitophagy Protein in Liver Mitochondria during Oxidative Stress and Sepsis

Authors
Piantadosi, CA; Tatro, LG; Suliman, HB
MLA Citation
Piantadosi, CA, Tatro, LG, and Suliman, HB. "Deconstructing Mitochondria: Co-localization of HO-1 and LC3II Mitophagy Protein in Liver Mitochondria during Oxidative Stress and Sepsis." 2010.
Source
wos-lite
Published In
Free Radical Biology & Medicine
Volume
49
Publish Date
2010
Start Page
S100
End Page
S100
DOI
10.1016/j.freeradbiomed.2010.10.263

THE HO/CO SYSTEM PROMOTES HEPATIC MITOCHONDRIAL BIOGENESIS DURING STAPHYLOCOCCUS AUREUS SEPSIS

Authors
MacGarvey, NC; Suliman, HB; Piantadosi, CA
MLA Citation
MacGarvey, NC, Suliman, HB, and Piantadosi, CA. "THE HO/CO SYSTEM PROMOTES HEPATIC MITOCHONDRIAL BIOGENESIS DURING STAPHYLOCOCCUS AUREUS SEPSIS." AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 181 (2010).
Source
wos-lite
Published In
American journal of respiratory and critical care medicine
Volume
181
Publish Date
2010

Extracellular superoxide dismutase regulates cardiac function and fibrosis.

Extracellular superoxide dismutase (EC-SOD) is an antioxidant that protects the heart from ischemia and the lung from inflammation and fibrosis. The role of cardiac EC-SOD under normal conditions and injury remains unclear. Cardiac toxicity, a common side effect of doxorubicin, involves oxidative stress. We hypothesize that EC-SOD is critical for normal cardiac function and protects the heart from oxidant-induced fibrosis and loss of function. C57BL/6 and EC-SOD-null mice were treated with doxorubicin, 15 mg/kg (i.p.). After 15 days, echocardiography was used to assess cardiac function. Left ventricle (LV) tissue was used to assess fibrosis and inflammation by staining, Western blot, and hydroxyproline analysis. At baseline, EC-SOD-null mice have LV wall thinning and increases in LV end diastolic dimensions compared to wild-type mice but have normal cardiac function. After doxorubicin, EC-SOD-null mice have decreases in fractional shortening not apparent in WT mice. Lack of EC-SOD also leads to increases in myocardial apoptosis and significantly more LV fibrosis and inflammatory cell infiltration. Administration of the metalloporphyrin AEOL 10150 abrogates the loss of cardiac function, and potentially fibrosis, associated with doxorubicin treatment in both wild-type and EC-SOD KO mice. EC-SOD is critical for normal cardiac morphology and protects the heart from oxidant-induced fibrosis, apoptosis, and loss of function. The antioxidant metalloporphyrin AEOL 10150 effectively protects cardiac function from doxorubicin-induced oxidative stress in vivo. These findings identify targets for the use of antioxidant agents in oxidant-induced cardiac fibrosis.

Authors
Kliment, CR; Suliman, HB; Tobolewski, JM; Reynolds, CM; Day, BJ; Zhu, X; McTiernan, CF; McGaffin, KR; Piantadosi, CA; Oury, TD
MLA Citation
Kliment, CR, Suliman, HB, Tobolewski, JM, Reynolds, CM, Day, BJ, Zhu, X, McTiernan, CF, McGaffin, KR, Piantadosi, CA, and Oury, TD. "Extracellular superoxide dismutase regulates cardiac function and fibrosis." J Mol Cell Cardiol 47.5 (November 2009): 730-742.
PMID
19695260
Source
pubmed
Published In
Journal of Molecular and Cellular Cardiology
Volume
47
Issue
5
Publish Date
2009
Start Page
730
End Page
742
DOI
10.1016/j.yjmcc.2009.08.010

Carbon monoxide, skeletal muscle oxidative stress, and mitochondrial biogenesis in humans.

Given that the physiology of heme oxygenase-1 (HO-1) encompasses mitochondrial biogenesis, we tested the hypothesis that the HO-1 product, carbon monoxide (CO), activates mitochondrial biogenesis in skeletal muscle and enhances maximal oxygen uptake (Vo(2max)) in humans. In 10 healthy subjects, we biopsied the vastus lateralis and performed Vo(2max) tests followed by blinded randomization to air or CO breathing (1 h/day at 100 parts/million for 5 days), a contralateral muscle biopsy on day 5, and repeat Vo(2max) testing on day 8. Six independent subjects underwent CO breathing and two muscle biopsies without exercise testing. Molecular studies were performed by real-time RT-PCR, Western blot analysis, and immunochemistry. After Vo(2max) testing plus CO breathing, significant increases were found in mRNA levels for nuclear respiratory factor-1, peroxisome proliferator-activated receptor-gamma coactivator-1alpha, mitochondrial transcription factor-A (Tfam), and DNA polymerase gamma (Polgamma) with no change in mitochondrial DNA (mtDNA) copy number or Vo(2max). Levels of myosin heavy chain I and nuclear-encoded HO-1, superoxide dismutase-2, citrate synthase, mitofusin-1 and -2, and mitochondrial-encoded cytochrome oxidase subunit-I (COX-I) and ATPase-6 proteins increased significantly. None of these responses were reproduced by Vo(2max) testing alone, whereas CO alone increased Tfam and Polgamma mRNA, and COX-I, ATPase-6, mitofusin-2, HO-1, and superoxide dismutase protein. These findings provide evidence linking the HO/CO response involved in mitochondrial biogenesis in rodents to skeletal muscle in humans through a set of responses involving regulation of the mtDNA transcriptosome and mitochondrial fusion proteins autonomously of changes in exercise capacity.

Authors
Rhodes, MA; Carraway, MS; Piantadosi, CA; Reynolds, CM; Cherry, AD; Wester, TE; Natoli, MJ; Massey, EW; Moon, RE; Suliman, HB
MLA Citation
Rhodes, MA, Carraway, MS, Piantadosi, CA, Reynolds, CM, Cherry, AD, Wester, TE, Natoli, MJ, Massey, EW, Moon, RE, and Suliman, HB. "Carbon monoxide, skeletal muscle oxidative stress, and mitochondrial biogenesis in humans." American journal of physiology. Heart and circulatory physiology 297.1 (July 2009): H392-H399. (Academic Article)
PMID
19465554
Source
manual
Published In
American journal of physiology. Heart and circulatory physiology
Volume
297
Issue
1
Publish Date
2009
Start Page
H392
End Page
H399

Nitric oxide synthase-2 induction optimizes cardiac mitochondrial biogenesis after endotoxemia.

Mitochondrial biogenesis protects metabolism from mitochondrial dysfunction produced by activation of innate immunity by lipopolysaccharide (LPS) or other bacterial products. Here we tested the hypothesis in mouse heart that activation of toll-like receptor-4 (TLR4), which induces early-phase genes that damage mitochondria, also activates mitochondrial biogenesis through induction of nitric oxide synthase (NOS2). We compared three strains of mice: wild type (Wt) C57BL/6J, TLR4(-/-), and NOS2(-/-)for cardiac mitochondrial damage and mitochondrial biogenesis by real-time RT-PCR, Western analysis, immunochemistry, and isoform analysis of myosin heavy chain (MHC) after sublethal heat-killed Escherichia coli (HkEC). After HkEC, Wt mice displayed significant myocardial mtDNA depletion along with enhanced TLR4 and NOS2 gene and protein expression that normalized in 72 h. HkEC generated less cytokine stress in TLR4(-/-)and NOS2(-/-)than Wt mice, NOS2(-/-)mice had mtDNA damage comparable to Wt, and both knockout strains failed to restore mtDNA copy number because of mitochondrial transcriptosome dysfunction. Wt mice also showed the largest beta-MHC isoform switch, but MHC recovery lagged in the NOS2(-/-)and TLR4(-/-)strains. The NOS2(-/-)mice also unexpectedly revealed the codependency of TLR4 expression on NOS2. These findings demonstrate the decisive participation of NOS2 induction by TLR4 in optimization of mitochondrial biogenesis and MHC expression after gram-negative challenge.

Authors
Reynolds, CM; Suliman, HB; Hollingsworth, JW; Welty-Wolf, KE; Carraway, MS; Piantadosi, CA
MLA Citation
Reynolds, CM, Suliman, HB, Hollingsworth, JW, Welty-Wolf, KE, Carraway, MS, and Piantadosi, CA. "Nitric oxide synthase-2 induction optimizes cardiac mitochondrial biogenesis after endotoxemia." Free Radic Biol Med 46.5 (March 1, 2009): 564-572.
PMID
19073249
Source
pubmed
Published In
Free Radical Biology and Medicine
Volume
46
Issue
5
Publish Date
2009
Start Page
564
End Page
572
DOI
10.1016/j.freeradbiomed.2008.11.007

Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1.

Heme oxygenase (HO)-1 is a protective antioxidant enzyme that prevents cardiomyocyte apoptosis, for instance, during progressive cardiomyopathy. Here we identify a fundamental aspect of the HO-1 protection mechanism by demonstrating that HO-1 activity in mouse heart stimulates the bigenomic mitochondrial biogenesis program via induction of NF-E2-related factor (Nrf)2 gene expression and nuclear translocation. Nrf2 upregulates the mRNA, protein, and activity for HO-1 as well as mRNA and protein for nuclear respiratory factor (NRF)-1. Mechanistically, in cardiomyocytes, endogenous carbon monoxide (CO) generated by HO-1 overexpression stimulates superoxide dismutase-2 upregulation and mitochondrial H(2)O(2) production, which activates Akt/PKB. Akt deactivates glycogen synthase kinase-3beta, which permits Nrf2 nuclear translocation and occupancy of 4 antioxidant response elements (AREs) in the NRF-1 promoter. The ensuing accumulation of nuclear NRF-1 protein leads to gene activation for mitochondrial biogenesis, which opposes apoptosis and necrosis caused by the cardio-toxic anthracycline chemotherapeutic agent, doxorubicin. In cardiac cells, Akt silencing exacerbates doxorubicin-induced apoptosis, and in vivo CO rescues wild-type but not Akt1(-/-) mice from doxorubicin cardiomyopathy. These findings consign HO-1/CO signaling through Nrf2 and Akt to the myocardial transcriptional program for mitochondrial biogenesis, provide a rationale for targeted mitochondrial CO therapy, and connect cardiac mitochondrial volume expansion with the inducible network of xenobiotic and antioxidant cellular defenses.

Authors
Piantadosi, CA; Carraway, MS; Babiker, A; Suliman, HB
MLA Citation
Piantadosi, CA, Carraway, MS, Babiker, A, and Suliman, HB. "Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1." Circ Res 103.11 (November 21, 2008): 1232-1240.
PMID
18845810
Source
pubmed
Published In
Circulation Research
Volume
103
Issue
11
Publish Date
2008
Start Page
1232
End Page
1240
DOI
10.1161/01.RES.0000338597.71702.ad

Lung EC-SOD overexpression attenuates hypoxic induction of Egr-1 and chronic hypoxic pulmonary vascular remodeling.

Although production of reactive oxygen species (ROS) such as superoxide (O(2)(.-)) has been implicated in chronic hypoxia-induced pulmonary hypertension (PH) and pulmonary vascular remodeling, the transcription factors and gene targets through which ROS exert their effects have not been completely identified. We used mice overexpressing the extracellular antioxidant enzyme extracellular superoxide dismutase (EC-SOD TG) to test the hypothesis that O(2)(.-) generated in the extracellular compartment under hypoxic conditions contributes to PH through the induction of the transcription factor, early growth response-1 (Egr-1), and its downstream gene target, tissue factor (TF). We found that chronic hypoxia decreased lung EC-SOD activity and protein expression in wild-type mice, but that EC-SOD activity remained five to seven times higher in EC-SOD TG mice under hypoxic conditions. EC-SOD overexpression attenuated chronic hypoxic PH, and vascular remodeling, measured by right ventricular systolic pressures, proliferation of cells in the vessel wall, muscularization of small pulmonary vessels, and collagen deposition. EC-SOD overexpression also prevented the early hypoxia-dependent upregulation of the redox-sensitive transcription factor Egr-1 and the procoagulant protein TF. These data provide the first evidence that EC-SOD activity is disrupted in chronic hypoxia, and increased EC-SOD activity can attenuate chronic hypoxic PH by limiting the hypoxic upregulation of redox-sensitive genes.

Authors
Nozik-Grayck, E; Suliman, HB; Majka, S; Albietz, J; Van Rheen, Z; Roush, K; Stenmark, KR
MLA Citation
Nozik-Grayck, E, Suliman, HB, Majka, S, Albietz, J, Van Rheen, Z, Roush, K, and Stenmark, KR. "Lung EC-SOD overexpression attenuates hypoxic induction of Egr-1 and chronic hypoxic pulmonary vascular remodeling." Am J Physiol Lung Cell Mol Physiol 295.3 (September 2008): L422-L430.
PMID
18599502
Source
pubmed
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
295
Issue
3
Publish Date
2008
Start Page
L422
End Page
L430
DOI
10.1152/ajplung.90293.2008

Transcriptional Regulation of SDHa flavoprotein by nuclear respiratory factor-1 prevents pseudo-hypoxia in aerobic cardiac cells.

Nuclear respiratory factor-1 (NRF-1) is integral to the transcriptional regulation of mitochondrial biogenesis, but its control over various respiratory genes overlaps other regulatory elements including those involved in O(2) sensing. Aerobic metabolism generally suppresses hypoxia-sensitive genes, e.g. via hypoxia-inducible factor-1 (HIF-1), but mutations in Complex II-succinate dehydrogenase (SDH), a tumor suppressor, stabilize HIF-1, producing pseudo-hypoxia. In aerobic cardiomyocytes, which rely on oxidative phosphorylation, we tested the hypothesis that NRF-1 regulates Complex II expression and opposes hypoxia-inducible factor-1. NRF-1 gene silencing blocked aerobic succinate oxidation, increasing nuclear HIF-1alpha protein prior to the loss of Complex I function. We postulated that NRF-1 suppression either specifically decreases the expression of one or more SDH subunits and increases succinate availability to regulate HIF-1 prolyl hydroxylases, or stimulates mitochondrial reactive oxygen production, which interferes with HIF-1alpha degradation. Using promoter analysis, gene silencing, and chromatin immunoprecipitation, NRF-1 was found to bind to the gene promoters of two of four nuclear-encoded Complex II subunits: SDHa and SDHd, but the enzyme activity was dynamically regulated through the catalytic SDHa flavoprotein. Complex II was inactivated by SDHa silencing, which led to aerobic HIF-1alpha stabilization, nuclear translocation, and enhanced expression of glucose transporters and heme oxygenase-1. This was unrelated to mitochondrial ROS production, reversible by high alpha-ketoglutarate concentrations, and coherent with regulation of HIF-1 by succinate reported in tumor cells. These findings disclose a novel role for NRF-1 in the transcriptional control of Complex II and prevention of pseudo-hypoxic gene expression in aerobic cardiac cells.

Authors
Piantadosi, CA; Suliman, HB
MLA Citation
Piantadosi, CA, and Suliman, HB. "Transcriptional Regulation of SDHa flavoprotein by nuclear respiratory factor-1 prevents pseudo-hypoxia in aerobic cardiac cells." J Biol Chem 283.16 (April 18, 2008): 10967-10977.
PMID
18252725
Source
pubmed
Published In
The Journal of biological chemistry
Volume
283
Issue
16
Publish Date
2008
Start Page
10967
End Page
10977
DOI
10.1074/jbc.M709741200

Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism.

The adaptive mechanisms that protect brain metabolism during and after hypoxia, for instance, during hypoxic preconditioning, are coordinated in part by nitric oxide (NO). We tested the hypothesis that acute transient hypoxia stimulates NO synthase (NOS)-activated mechanisms of mitochondrial biogenesis in the hypoxia-sensitive subcortex of wild-type (Wt) and neuronal NOS (nNOS) and endothelial NOS (eNOS)-deficient mice. Mice were exposed to hypobaric hypoxia for 6 h, and changes in immediate hypoxic transcriptional regulation of mitochondrial biogenesis was assessed in relation to mitochondrial DNA (mtDNA) content and mitochondrial density. There were no differences in cerebral blood flow or hippocampal PO2 responses to acute hypoxia among these strains of mice. In Wt mice, hypoxia increased mRNA levels for peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1 alpha), nuclear respiratory factor-1, and mitochondrial transcription factor A. After 24 h, new mitochondria, localized in reporter mice expressing mitochondrial green fluorescence protein, were seen primarily in hippocampal neurons. eNOS-/- mice displayed lower basal levels but maintained hypoxic induction of these transcripts. In contrast, nuclear transcriptional regulation of mitochondrial biogenesis in nNOS-/- mice was normal at baseline but did not respond to hypoxia. After hypoxia, subcortical mtDNA content increased in Wt and eNOS-/- mice but not in nNOS-/- mice. Hypoxia stimulated PGC-1alpha protein expression and phosphorylation of protein kinase A and cAMP response element binding (CREB) protein in Wt mice, but CREB only was activated in eNOS-/- mice and not in nNOS-/- mice. These findings demonstrate that hypoxic preconditioning elicits subcortical mitochondrial biogenesis by a novel mechanism that requires nNOS regulation of PGC-1alpha and CREB.

Authors
Gutsaeva, DR; Carraway, MS; Suliman, HB; Demchenko, IT; Shitara, H; Yonekawa, H; Piantadosi, CA
MLA Citation
Gutsaeva, DR, Carraway, MS, Suliman, HB, Demchenko, IT, Shitara, H, Yonekawa, H, and Piantadosi, CA. "Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism." J Neurosci 28.9 (February 27, 2008): 2015-2024.
PMID
18305236
Source
pubmed
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
28
Issue
9
Publish Date
2008
Start Page
2015
End Page
2024
DOI
10.1523/JNEUROSCI.5654-07.2008

Mitochondrial biogenesis in the pulmonary vasculature during inhalational lung injury and fibrosis.

Cell survival and injury repair is facilitated by mitochondrial biogenesis; however, the role of this process in lung repair is unknown. We evaluated mitochondrial biogenesis in the mouse lung in two injuries that cause acute inflammation and in two that cause chronic inflammation and pulmonary fibrosis. By using reporter mice that express green fluorescent protein (GFP) exclusively in mitochondria, we tracked mitochondrial biogenesis and correlated it with histologic lung injury, proliferation, and fibrosis. At 72 hours after acute LPS or continuous exposure to hyperoxia (Fio2, 1.0), the lungs showed diffuse infiltration by inflammatory cells in the alveolar region. In reporter mice, patchy new mitochondrial fluorescence was found in the alveolar region but was most prominent and unexpected in perivascular regions. At 14 days after instillation of asbestos or bleomycin, diffuse chronic inflammation had developed, and green fluorescence appeared in inflammatory cells in the expanded interstitium and was most intense in smooth muscle cells of pulmonary vessels. In all four lung injuries, mitochondrial fluorescence colocalized with mitochondrial superoxide dismutase, but not with proliferating cell nuclear antigen. These data indicate that vascular mitochondrial biogenesis is activated in diverse inhalational lung injuries along with oxidative stress. This finding indicates a unique and unexpected mechanism of metabolic adaptation to pulmonary fibrotic injuries.

Authors
Carraway, MS; Suliman, HB; Kliment, C; Welty-Wolf, KE; Oury, TD; Piantadosi, CA
MLA Citation
Carraway, MS, Suliman, HB, Kliment, C, Welty-Wolf, KE, Oury, TD, and Piantadosi, CA. "Mitochondrial biogenesis in the pulmonary vasculature during inhalational lung injury and fibrosis." Antioxid Redox Signal 10.2 (February 2008): 269-275.
PMID
17999632
Source
pubmed
Published In
Antioxidants & Redox Signaling
Volume
10
Issue
2
Publish Date
2008
Start Page
269
End Page
275
DOI
10.1089/ars.2007.1910

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy.

The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis.

Authors
Suliman, HB; Carraway, MS; Ali, AS; Reynolds, CM; Welty-Wolf, KE; Piantadosi, CA
MLA Citation
Suliman, HB, Carraway, MS, Ali, AS, Reynolds, CM, Welty-Wolf, KE, and Piantadosi, CA. "The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy." J Clin Invest 117.12 (December 2007): 3730-3741.
Website
http://hdl.handle.net/10161/13989
PMID
18037988
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
117
Issue
12
Publish Date
2007
Start Page
3730
End Page
3741
DOI
10.1172/JCI32967

Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis.

RATIONALE: The extent, timing, and significance of mitochondrial injury and recovery in bacterial sepsis are poorly characterized, although oxidative and nitrosative mitochondrial damage have been implicated in the development of organ failure. OBJECTIVES: To define the relationships between mitochondrial biogenesis, oxidative metabolism, and recovery from Staphylococcus aureus sepsis. METHODS: We developed a murine model of fibrin clot peritonitis, using S. aureus. The model yielded dose-dependent decreases in survival and resting energy expenditure, allowing us to study recovery from sublethal sepsis. MEASUREMENTS AND MAIN RESULTS: Peritonitis caused by 10(6) colony-forming units of S. aureus induced a low tumor necrosis factor-alpha state and minimal hepatic cell death, but activated prosurvival protein kinase A, B, and C sequentially over 3 days. Basal metabolism by indirect calorimetry was depressed because of selective mitochondrial oxidative stress and subsequent loss of mitochondrial DNA copy number. During recovery, mitochondrial biogenesis was strongly activated by regulated expression of the requisite nuclear respiratory factors 1 and 2 and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha, as well as by repression of the biogenesis suppressor nuclear receptor interacting protein-140. Biogenesis reconstituted mitochondrial DNA copy number and transcription, and restored basal metabolism without significant hepatocellular proliferation. These events dramatically increased hepatic mitochondrial density in transgenic mice expressing mitochondrially targeted green fluorescent protein. CONCLUSIONS: This is the first demonstration that mitochondrial biogenesis restores oxidative metabolism in bacterial sepsis and is therefore an early and important prosurvival factor.

Authors
Haden, DW; Suliman, HB; Carraway, MS; Welty-Wolf, KE; Ali, AS; Shitara, H; Yonekawa, H; Piantadosi, CA
MLA Citation
Haden, DW, Suliman, HB, Carraway, MS, Welty-Wolf, KE, Ali, AS, Shitara, H, Yonekawa, H, and Piantadosi, CA. "Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis." Am J Respir Crit Care Med 176.8 (October 15, 2007): 768-777.
PMID
17600279
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
176
Issue
8
Publish Date
2007
Start Page
768
End Page
777
DOI
10.1164/rccm.200701-161OC

A new activating role for CO in cardiac mitochondrial biogenesis.

To investigate a possible new physiological role of carbon monoxide (CO), an endogenous gas involved in cell signaling and cytotoxicity, we tested the hypothesis that the mitochondrial generation of reactive oxygen species by CO activates mitochondrial biogenesis in the heart. In mice, transient elevations of cellular CO by five- to 20-fold increased the copy number of cardiac mitochondrial DNA, the content of respiratory complex I-V and interfibrillar mitochondrial density within 24 hours. Mitochondrial biogenesis is activated by gene and protein expression of the nuclear respiratory factor 1 (NRF1) and NRF2, of peroxisome proliferator-activated receptor gamma co-activator-1alpha, and of mitochondrial transcription factor A (TFAM), which augmented the copy number of mitochondrial DNA (mtDNA). This is independent of nitric oxide synthase (NOS), as demonstrated by the identical responses in wild-type and endothelial NOS (eNOS)-deficient mice, and by the inhibition of inducible NOS (iNOS). In the heart and in isolated cardiomyocytes, CO activation involved both guanylate cyclase and the pro-survival kinase Akt/PKB. Akt activation was facilitated by mitochondrial binding of CO and by production of hydrogen peroxide (H(2)O(2)). Interference with Akt activity by blocking PI 3-kinase and by mitochondrial targeting of catalase to scavenge H(2)O(2) prevented binding of NRF1 to the Tfam promoter, thereby connecting mitochondrial H(2)O(2) to the pathway leading to mtDNA replication. The findings disclose mitochondrial CO and H(2)O(2) as new activating factors in cardiac mitochondrial biogenesis.

Authors
Suliman, HB; Carraway, MS; Tatro, LG; Piantadosi, CA
MLA Citation
Suliman, HB, Carraway, MS, Tatro, LG, and Piantadosi, CA. "A new activating role for CO in cardiac mitochondrial biogenesis." J Cell Sci 120.Pt 2 (January 15, 2007): 299-308.
PMID
17179207
Source
pubmed
Published In
Journal of cell science
Volume
120
Issue
Pt 2
Publish Date
2007
Start Page
299
End Page
308
DOI
10.1242/jcs.03318

Protecting the permeability pore and mitochondrial biogenesis.

Recent evidence links the pathogenesis of multiple organ dysfunction syndrome (MODS) in sepsis to mitochondrial damage. Our hypothesis is that cellular mechanisms maintaining mitochondrial function must be protected in order to prevent MODS. Recent animal experiments indicate that host defences which target and kill microbes, in part via reactive oxygen and nitrogen production, also injure mitochondria, thus activating mitochondrial cell death pathways. To limit such collateral damage, the cell up-regulates and imports into mitochondria several nuclear-encoded proteins for antioxidant defence and mitochondrial DNA (mtDNA) replication. Fully integrated responses lead to mitochondrial biogenesis, which may alter cellular phenotype to avoid mitochondrial permeability transition, apoptosis, or energy failure. Key to the cell's vulnerability to oxidant generation by the innate immune response is the mtDNA content. MtDNA depletion is opposed by oxidation reduction (redox) signals that communicate the extent of mitochondrial damage to the nucleus. Molecular studies suggest that redox mechanisms activate two biogenic transcription factors, nuclear respiratory factors 1 and 2, which forestall a deterioration of oxidative phosphorylation during infection. Biogenic failure or an intrinsic biogenic arrest could hasten degradation of mitochondrial function and drive the cell to apoptosis or necrosis. By implication, novel protective strategies for biogenesis hold promise for the prevention of MODS.

Authors
Piantadosi, CA; Carraway, MS; Haden, DW; Suliman, HB
MLA Citation
Piantadosi, CA, Carraway, MS, Haden, DW, and Suliman, HB. "Protecting the permeability pore and mitochondrial biogenesis." Novartis Found Symp 280 (2007): 266-276. (Review)
PMID
17380800
Source
pubmed
Published In
Novartis Foundation Symposium
Volume
280
Publish Date
2007
Start Page
266
End Page
276

Erythropoietin promotes cardiac mitochondrial biogenesis through Akt activation

Authors
Carraway, MS; Suliman, HB; Piantadosi, CA
MLA Citation
Carraway, MS, Suliman, HB, and Piantadosi, CA. "Erythropoietin promotes cardiac mitochondrial biogenesis through Akt activation." 2007.
Source
wos-lite
Published In
Free Radical Biology & Medicine
Volume
43
Publish Date
2007
Start Page
S148
End Page
S148

Skeletal muscle mitochondrial biogenesis induced by carbon monoxide

Authors
Suliman, HB; Rhodes, M; Moon, RE; Carraway, MS; Piantadosi, CA
MLA Citation
Suliman, HB, Rhodes, M, Moon, RE, Carraway, MS, and Piantadosi, CA. "Skeletal muscle mitochondrial biogenesis induced by carbon monoxide." 2007.
Source
wos-lite
Published In
Free Radical Biology & Medicine
Volume
43
Publish Date
2007
Start Page
S72
End Page
S72

Nitric oxide and toll-like receptor 4 are required for cardiac mitochondrial biogenesis after endotoxemia

Authors
Reynolds, CM; Suliman, HB; Carraway, MS; Hollingsworth, JW; Welty-Wolf, KE; Piantadosi, CA
MLA Citation
Reynolds, CM, Suliman, HB, Carraway, MS, Hollingsworth, JW, Welty-Wolf, KE, and Piantadosi, CA. "Nitric oxide and toll-like receptor 4 are required for cardiac mitochondrial biogenesis after endotoxemia." 2007.
Source
wos-lite
Published In
Free Radical Biology & Medicine
Volume
43
Publish Date
2007
Start Page
S144
End Page
S144

Heme oxygenase-1 supports mitochondrial function and protects against doxorubicin toxicity via the Pi3K/Akt pathway

Authors
Piantadosi, CA; Suliman, HB
MLA Citation
Piantadosi, CA, and Suliman, HB. "Heme oxygenase-1 supports mitochondrial function and protects against doxorubicin toxicity via the Pi3K/Akt pathway." 2007.
Source
wos-lite
Published In
Free Radical Biology & Medicine
Volume
43
Publish Date
2007
Start Page
S157
End Page
S157

Metabolic capacity regulates iron homeostasis in endothelial cells.

The sensitivity of endothelial cells to oxidative stress and the high concentrations of iron in mitochondria led us to test the hypotheses that (1) changes in respiratory capacity alter iron homeostasis, and (2) lack of aerobic metabolism decreases labile iron stores and attenuates oxidative stress. Two respiration-deficient (rho(o)) endothelial cell lines with selective deletion of mitochondrial DNA (mtDNA) were created by exposing a parent endothelial cell line (EA) to ethidium bromide. Surviving cells were cloned and mtDNA-deficient cell lines were demonstrated to have diminished oxygen consumption. Total cellular and mitochondrial iron levels were measured, and iron uptake and compartmentalization were measured by inductively coupled plasma atomic emission spectroscopy. Iron transport and storage protein expression were analyzed by real-time polymerase chain reaction and Western blot or ELISA, and total and mitochondrial reactive oxygen species (ROS) generation was measured. Mitochondrial iron content was the same in all three cell lines, but both rho(o) lines had lower iron uptake and total cellular iron. Protein and mRNA expressions of major cytosolic iron transport constituents were down-regulated in rho(o) cells, including transferrin receptor, divalent metal transporter-1 (-IRE isoform), and ferritin. The mitochondrial iron-handling protein, frataxin, was also decreased in respiration-deficient cells. The rho(o) cell lines generated less mitochondrial ROS but released more extracellular H(2)O(2), and demonstrated significantly lower levels of lipid aldehyde formation than control cells. In summary, rho(o) cells with a minimal aerobic capacity had decreased iron uptake and storage. This work demonstrates that mitochondria regulate iron homeostasis in endothelial cells.

Authors
Carraway, MS; Suliman, HB; Madden, MC; Piantadosi, CA; Ghio, AJ
MLA Citation
Carraway, MS, Suliman, HB, Madden, MC, Piantadosi, CA, and Ghio, AJ. "Metabolic capacity regulates iron homeostasis in endothelial cells." Free Radic Biol Med 41.11 (December 1, 2006): 1662-1669.
PMID
17145554
Source
pubmed
Published In
Free Radical Biology & Medicine
Volume
41
Issue
11
Publish Date
2006
Start Page
1662
End Page
1669
DOI
10.1016/j.freeradbiomed.2006.09.005

Carbon monoxide, oxidative stress, and mitochondrial permeability pore transition.

The cellular effects of carbon monoxide (CO) are produced primarily by CO binding to iron or other transition metals, which may also promote prooxidant activities of the more reactive gases, oxygen and nitric oxide. We tested the hypothesis that prooxidant effects of CO deregulate the calcium-dependent mitochondrial pore transition (MPT), which disrupts membrane potential and releases apoptogenic proteins. Rats were exposed to either CO (50 ppm) or hypobaric hypoxia (HH) for 1, 3, or 7 days, and liver mitochondria harvested to study protein expression and sensitivity to MPT by calcium and oxidants. Both exposures induced hypoxia-sensitive protein expression: hypoxia-inducible factor 1alpha (HIF-1alpha), heme oxygenase-1 (HO-1), and manganese SOD (SOD2), but SOD2 induction was greater by CO than by HH, especially at 7 days. Relative to HH, CO also caused significant early mitochondrial oxidative and nitrosative stress shown by decreases in GSH/GSSG and increases in protein 3-nitrotyrosine (3-NT) and protein mixed disulfide formation. This altered MPT sensitivity to calcium through an effect on the "S-site," causing loss of pore protection by adenine nucleotides. By 7 days, despite continued CO, nitrosative stress decreased and adenine nucleotide protection was restored to preexposure levels. This is the first evidence of functional mitochondrial pore stress caused by CO independently of its hypoxic effect, as well as a compensatory response exemplifying a mitochondrial phenotype shift. The implications are that cellular CO can activate or deactivate mitochondria for initiation of apoptosis in vivo.

Authors
Piantadosi, CA; Carraway, MS; Suliman, HB
MLA Citation
Piantadosi, CA, Carraway, MS, and Suliman, HB. "Carbon monoxide, oxidative stress, and mitochondrial permeability pore transition." Free Radic Biol Med 40.8 (April 15, 2006): 1332-1339.
PMID
16631523
Source
pubmed
Published In
Free Radical Biology & Medicine
Volume
40
Issue
8
Publish Date
2006
Start Page
1332
End Page
1339
DOI
10.1016/j.freeradbiomed.2005.11.020

Glutathione regulates susceptibility to oxidant-induced mitochondrial DNA damage in human lymphocytes.

Oxidative damage to mitochondrial DNA (mtDNA) interferes with the expression of mitochondrial-encoded subunits of the electron transport complexes of oxidative phosphorylation. MtDNA is protected by several mitochondrial antioxidant systems, but the specific importance of glutathione is unknown. We hypothesized that glutathione protects mtDNA from oxidative damage in human blood lymphocytes and that glutathione depletion increases susceptibility to mtDNA depletion, which increases vulnerability to apoptosis. MtDNA damage was measured in human blood lymphocytes exposed to tert-butyl-hydroperoxide (t-BOOH) or t-BOOH plus the glutathione analog, glutathione ethyl ester (GEE). Mitochondrial oxidative stress, mtDNA damage, and susceptibility to apoptosis were analyzed after glutathione depletion with buthionine sulfoximine (BSO). The data show selective damage to lymphocyte mtDNA at low concentrations of tBOOH that is attenuated by glutathione supplementation. Moreover, inhibition of glutathione synthesis led to lymphocyte ROS generation and mtDNA damage, and increased susceptibility to receptor-mediated apoptosis. These findings implicate the glutathione system in maintaining mtDNA integrity and resistance to apoptosis in lymphocytes and suggest that assessment of mtDNA damage in blood lymphocytes may be a useful marker of oxidative stress in humans.

Authors
Hollins, DL; Suliman, HB; Piantadosi, CA; Carraway, MS
MLA Citation
Hollins, DL, Suliman, HB, Piantadosi, CA, and Carraway, MS. "Glutathione regulates susceptibility to oxidant-induced mitochondrial DNA damage in human lymphocytes." Free Radic Biol Med 40.7 (April 1, 2006): 1220-1226.
PMID
16545690
Source
pubmed
Published In
Free Radical Biology & Medicine
Volume
40
Issue
7
Publish Date
2006
Start Page
1220
End Page
1226
DOI
10.1016/j.freeradbiomed.2005.11.011

A comparison of hyperbaric oxygen versus hypoxic cerebral preconditioning in neonatal rats.

The potency of hyperbaric preconditioning (HBO-PC) is uncertain compared to well-validated ischemic or hypoxic models and no studies have directly compared HBO-PC to hypoxic preconditioning (HPC). We subjected rat pups to unilateral carotid cauterization followed by 90 min (min) of hypoxia using 8% O(2). Three HBO-PC regimes (maximum 2.5 atmospheres for 150 min) were compared to HPC (150 min of 8% O(2)) for changes in mortality and brain weight. Preconditioning-induced oxidative stress was assessed using aconitase activity and manganese superoxide dismutase (MnSOD) transcript levels. Initial brain weight data revealed a large coefficient of variation and compelled an examination of the temperature sensitivity of the model that revealed a narrow optimal range of 35 to 37 degrees C of variability in brain injury and mortality. With rigorous temperature control, high dose HBO-PC and HPC showed comparable anatomic (mean hemispheric weight decrease: control 42%, HPC 25% (P=0.01), HBO-PC 26% (P=0.01) and mortality protection (control 14.7%, HPC 5.9% HBO-PC 5.7%, P=0.001). High dose HBO-PC, but not HPC, suppressed aconitase activity by 65% at 24 h after the preconditioning stimulus (P=0.001). In contrast, MnSOD mRNA increased 2.5-fold at 24 h after HPC (P=0.007) but not after high dose HBO-PC. Thus, when temperature variability is eliminated, HBO-PC and HPC elicit similar preconditioning efficacy in neonatal brain but invoke different defenses against oxidative stress.

Authors
Freiberger, JJ; Suliman, HB; Sheng, H; McAdoo, J; Piantadosi, CA; Warner, DS
MLA Citation
Freiberger, JJ, Suliman, HB, Sheng, H, McAdoo, J, Piantadosi, CA, and Warner, DS. "A comparison of hyperbaric oxygen versus hypoxic cerebral preconditioning in neonatal rats." Brain Res 1075.1 (February 23, 2006): 213-222.
PMID
16458861
Source
pubmed
Published In
Brain Research
Volume
1075
Issue
1
Publish Date
2006
Start Page
213
End Page
222
DOI
10.1016/j.brainres.2005.12.088

Mitochondrial transcription factor A induction by redox activation of nuclear respiratory factor 1.

The nuclear expression of mitochondrial transcription factor A (Tfam), which is required for mitochondrial DNA (mtDNA) transcription and replication, must be linked to cellular energy needs. Because respiration generates reactive oxygen species as a side-product, we tested the idea that reactive oxygen species regulate Tfam expression through phosphorylation of nuclear respiratory factor (NRF-1) and binding to the Tfam promoter. In mitochondria-rich rat hepatoma cells that overexpress NRF-1, basal and oxidant-induced increases were found in Tfam expression and mtDNA content. Specific binding of NRF-1 to Tfam promoter was demonstrated by electrophoretic mobility shift assay and chromatin immunoprecipitation. NRF-1-Tfam binding was augmented under pro-oxidant conditions. NRF-1 gene silencing produced 1:1 knockdown of Tfam expression and decreased mtDNA content. To evaluate oxidation-reduction (redox) regulation of NRF-1 in Tfam expression, blockade of upstream phosphatidylinositol 3-kinase was used to demonstrate loss of oxidant stimulation of NRF-1 phosphorylation and Tfam expression. The oxidant response was also abrogated by specific inhibition of Akt/protein kinase B. Examination of the NRF-1 amino acid sequence revealed an Akt phosphorylation consensus at which site-directed mutagenesis abolished NRF-1 phosphorylation by Akt. Finally, Akt phosphorylation and NRF-1 translocation predictably lacked oxidant regulation in a cancer line having no PTEN tumor suppressor (HCC1937 cells). This study discloses novel redox regulation of NRF-1 phosphorylation and nuclear translocation by phosphatidylinositol 3,4,5-triphosphate kinase/Akt signaling in controlling Tfam induction by an anti-oxidant pro-survival network.

Authors
Piantadosi, CA; Suliman, HB
MLA Citation
Piantadosi, CA, and Suliman, HB. "Mitochondrial transcription factor A induction by redox activation of nuclear respiratory factor 1." J Biol Chem 281.1 (January 6, 2006): 324-333.
PMID
16230352
Source
pubmed
Published In
The Journal of biological chemistry
Volume
281
Issue
1
Publish Date
2006
Start Page
324
End Page
333
DOI
10.1074/jbc.M508805200

Oxygen-induced mitochondrial biogenesis in the rat hippocampus.

The hypothesis that damage to mitochondrial DNA by reactive oxygen species increases the activity of nuclear and mitochondrial transcription factors for mitochondrial DNA replication was tested in the in vivo rat brain. Mitochondrial reactive oxygen species generation was stimulated using pre-convulsive doses of hyperbaric oxygen and hippocampal mitochondrial DNA content and neuronal and mitochondrial morphology and cell proliferation were evaluated at 1, 5 and 10 days. Gene expression was subsequently evaluated to assess nuclear and mitochondrial-encoded respiratory genes, mitochondrial transcription factor A, and nuclear respiratory transcription factors-1 and -2. After 1 day, a mitochondrial DNA deletion emerged involving Complex I and IV subunit-encoding regions that was independent of overt neurological or cytological O(2) toxicity, and resolved before the onset of cell proliferation. This damage was attenuated by blockade of neuronal nitric oxide synthase. Compensatory responses were found in nuclear gene expression for manganese superoxide dismutase, mitochondrial transcription factor A, and nuclear respiratory transcription factor-2. Enhanced nuclear respiratory transcription factor-2 binding activity in hippocampus was accompanied by a nearly three-fold boost in mitochondrial DNA content over 5 days. The finding that O(2) activates regional mitochondrial DNA transcription, replication, and mitochondrial biogenesis in the hippocampus may have important implications for maintaining neuronal viability after brain injury.

Authors
Gutsaeva, DR; Suliman, HB; Carraway, MS; Demchenko, IT; Piantadosi, CA
MLA Citation
Gutsaeva, DR, Suliman, HB, Carraway, MS, Demchenko, IT, and Piantadosi, CA. "Oxygen-induced mitochondrial biogenesis in the rat hippocampus." Neuroscience 137.2 (2006): 493-504.
PMID
16298077
Source
pubmed
Published In
Neuroscience
Volume
137
Issue
2
Publish Date
2006
Start Page
493
End Page
504
DOI
10.1016/j.neuroscience.2005.07.061

Carbon monoxide protects against mitochondrial damage in doxorubicin-induced myocardial dysfunction

Authors
Suliman, HB; Carraway, MS; Welty-Wolf, KE; Piantadosi, CA
MLA Citation
Suliman, HB, Carraway, MS, Welty-Wolf, KE, and Piantadosi, CA. "Carbon monoxide protects against mitochondrial damage in doxorubicin-induced myocardial dysfunction." 2006.
Source
wos-lite
Published In
Free Radical Biology & Medicine
Volume
41
Publish Date
2006
Start Page
S152
End Page
S152

Mitochondrial biogenesis in sepsis: a role for inducible nitric oxide synthase

Authors
Babiker, AS; Suliman, HB; Carraway, MS; Welty-Wolf, KE; Piantadosi, CA
MLA Citation
Babiker, AS, Suliman, HB, Carraway, MS, Welty-Wolf, KE, and Piantadosi, CA. "Mitochondrial biogenesis in sepsis: a role for inducible nitric oxide synthase." 2006.
Source
wos-lite
Published In
Free Radical Biology & Medicine
Volume
41
Publish Date
2006
Start Page
S47
End Page
S47

NOX4 mediates thrombin signaling in endothelial cells

Authors
Carraway, MS; Whorton, R; Suliman, HB; Babiker, A-W; Piantadosi, CA
MLA Citation
Carraway, MS, Whorton, R, Suliman, HB, Babiker, A-W, and Piantadosi, CA. "NOX4 mediates thrombin signaling in endothelial cells." 2006.
Source
wos-lite
Published In
Free Radical Biology & Medicine
Volume
41
Publish Date
2006
Start Page
S119
End Page
S119

Extracellular superoxide dismutase.

The extracellular space is protected from oxidant stress by the antioxidant enzyme extracellular superoxide dismutase (EC-SOD), which is highly expressed in selected tissues including blood vessels, heart, lungs, kidney and placenta. EC-SOD contains a unique heparin-binding domain at its carboxy-terminus that establishes localization to the extracellular matrix where the enzyme scavenges superoxide anion. The EC-SOD heparin-binding domain can be removed by proteolytic cleavage, releasing active enzyme into the extracellular fluid. In addition to protecting against extracellular oxidative damage, EC-SOD, by scavenging superoxide, preserves nitric oxide bioactivity and facilitates hypoxia-induced gene expression. Loss of EC-SOD activity contributes to the pathogenesis of a number of diseases involving tissues with high levels of constitutive extracellular superoxide dismutase expression. A thorough understanding of the biological role of EC-SOD will be invaluable for developing novel therapies to prevent stress by extracellular oxidants.

Authors
Nozik-Grayck, E; Suliman, HB; Piantadosi, CA
MLA Citation
Nozik-Grayck, E, Suliman, HB, and Piantadosi, CA. "Extracellular superoxide dismutase." Int J Biochem Cell Biol 37.12 (December 2005): 2466-2471. (Review)
PMID
16087389
Source
pubmed
Published In
The International Journal of Biochemistry & Cell Biology
Volume
37
Issue
12
Publish Date
2005
Start Page
2466
End Page
2471
DOI
10.1016/j.biocel.2005.06.012

Cholestyramine feeding lowers number of colonic apoptotic cells in rat.

Secondary bile acids that are formed in the colon by bacterial action have the potential property of eliciting pathological conditions. Apoptosis of mucosal epithelial cells is recognized as an adaptation that may counteract such pathologies. Cholestyramine, an anion exchange resin that sequesters bile salts in the gut, could decrease levels of secondary bile salt stress and thus conserve the potency of the protective action. Two groups of rats were studied: those fed 4% cholestyramine and those fed regular rat food. Rats were fed cholestyramine for 7, 14, 21, or 28 d. All animals were evaluated for cell death (apoptosis) using in situ TUNEL staining, and confirmed with single-stranded DNA (ssDNA). The effect of cholestyramine on the proliferating cell nuclear antigen (PCNA) in colonic crypt cells was also examined. Our data shows that animals fed cholestyramine for 28 d show evidence of a significant decrease in the levels of apoptotic cells in their large intestines, particularly goblet cells, when compared with the control animals and no change in cell proliferation. Thus, cholestyramine may serve as an alternative in attenuating apoptosis associated with inflammatory disorders that can result in significant enterocyte and goblet-cell death.

Authors
Lack, L; Suliman, HB; Rahman, AA; Abou-Donia, MB
MLA Citation
Lack, L, Suliman, HB, Rahman, AA, and Abou-Donia, MB. "Cholestyramine feeding lowers number of colonic apoptotic cells in rat." J Toxicol Environ Health A 68.22 (November 26, 2005): 1963-1975.
PMID
16263689
Source
pubmed
Published In
Journal of Toxicology & Environmental Health: Part A
Volume
68
Issue
22
Publish Date
2005
Start Page
1963
End Page
1975
DOI
10.1080/15287390500227050

Toll-like receptor 4 mediates mitochondrial DNA damage and biogenic responses after heat-inactivated E. coli.

An important site of cellular damage in bacterial sepsis is mitochondrial DNA (mtDNA), which we proposed is caused by reactive oxygen and nitrogen species generated by activation of signaling through specific toll-like receptors (TLR). In wild-type (Wt) mice injected with heat-inactivated E. coli, hepatic TLR4 and TLR2 proteins were up-regulated with TLR-dependent increases in transcript levels for tumor necrosis factor (TNF-alpha), interleukin 6, nitric oxide synthase-II (iNOS), and NADPH oxidase 2 (Nox2). The accompanying stress significantly depleted hepatic mtDNA despite eight- and fourfold increases in manganese superoxide dismutase (MnSOD) and mitochondrial transcription factor A (Tfam) expression, respectively. The identical E. coli dose generated significantly less TNF-alpha, NO, and Nox2 in TLR4-/- and TLR2/4-/- but not in TLR2-/- mice. TLR4-/- and TLR2/4-/- compared with Wt mice were protected from mtDNA oxidation but showed no Tfam up-regulation and little copy number restoration. A critical role in the mtDNA damage was determined for TLR4-mediated iNOS transcription through the MyD88 pathway. In Wt mice, mtDNA depletion was avoided by selective iNOS blockade, and residual mtDNA loss was linked to NF-kappaB-dependent TNF-alpha expression. These data disclose the dual role of TLR4 in mtDNA damage and compensatory mitochondrial biogenic responses after innate immune activation.

Authors
Suliman, HB; Welty-Wolf, KE; Carraway, MS; Schwartz, DA; Hollingsworth, JW; Piantadosi, CA
MLA Citation
Suliman, HB, Welty-Wolf, KE, Carraway, MS, Schwartz, DA, Hollingsworth, JW, and Piantadosi, CA. "Toll-like receptor 4 mediates mitochondrial DNA damage and biogenic responses after heat-inactivated E. coli." FASEB J 19.11 (September 2005): 1531-1533.
PMID
15994412
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
19
Issue
11
Publish Date
2005
Start Page
1531
End Page
1533
DOI
10.1096/fj.04-3500fje

Carbon monoxide actuates O(2)-limited heme degradation in the rat brain.

The biochemical paradigm for carbon monoxide (CO) is driven by the century-old Warburg hypothesis: CO alters O(2)-dependent functions by binding heme proteins in competitive relation to 1/oxygen partial pressure (PO(2)). High PO(2) thus hastens CO elimination and toxicity resolution, but with more O(2), CO-exposed tissues paradoxically experience less oxidative stress. To help resolve this paradox we tested the Warburg hypothesis using a highly sensitive gas-reduction method to track CO uptake and elimination in brain, heart, and skeletal muscle in situ during and after exogenous CO administration. We found that CO administration does increase tissue CO concentration, but not in strict relation to 1/PO(2). Tissue gas uptake and elimination lag behind blood CO as predicted, but 1/PO(2) vs. [CO] fails even at hyperbaric PO(2). Mechanistically, we established in the brain that cytosol heme concentration increases 10-fold after CO exposure, which sustains intracellular CO content by providing substrate for heme oxygenase (HO) activated after hypoxia when O(2) is resupplied to cells rich in reduced pyridine nucleotides. We further demonstrate by analysis of CO production rates that this heme stress is not due to HO inhibition and that heme accumulation is facilitated by low brain PO(2). The latter becomes rate limiting for HO activity even at physiological PO(2), and the heme stress leads to doubling of brain HO-1 protein. We thus reveal novel biochemical actions of both CO and O(2) that must be accounted for when evaluating oxidative stress and biological signaling by these gases.

Authors
Cronje, FJ; Carraway, MS; Freiberger, JJ; Suliman, HB; Piantadosi, CA
MLA Citation
Cronje, FJ, Carraway, MS, Freiberger, JJ, Suliman, HB, and Piantadosi, CA. "Carbon monoxide actuates O(2)-limited heme degradation in the rat brain." Free Radic Biol Med 37.11 (December 1, 2004): 1802-1812.
PMID
15528039
Source
pubmed
Published In
Free Radical Biology & Medicine
Volume
37
Issue
11
Publish Date
2004
Start Page
1802
End Page
1812
DOI
10.1016/j.freeradbiomed.2004.08.022

Lipopolysaccharide induces oxidative cardiac mitochondrial damage and biogenesis.

OBJECTIVE: The responses to bacterial lipopolysaccharide (LPS) damage mitochondria by generating oxidative stress within the organelles. We postulated that LPS damages heart mitochondrial DNA and protein by oxidation, and that this is recovered by oxidative mechanisms of mitochondrial biogenesis. METHODS AND RESULTS: Systemic crude E. coli LPS administration decreased mtDNA copy number and mtDNA gene transcription in rat heart caused by oxidant deletion of mtDNA. The fall in copy number was reflected in proteomic expression of several mitochondria-encoded subunits of Complexes I, IV, and V. Recovery of mtDNA copy number involved biogenesis as indicated by mitochondrial transcription factor A (Tfam) and DNA polymerase-gamma expression. The transcriptional response also included nuclear accumulation of peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1) and mRNA expression for redox-regulated nuclear respiratory factors (NRF-1 and -2). CONCLUSIONS: These novel findings disclose a duality of reactive oxygen species (ROS) effect in the heart's response to LPS in which oxidative mitochondrial damage is opposed by oxidant stimulation of biogenesis.

Authors
Suliman, HB; Welty-Wolf, KE; Carraway, M; Tatro, L; Piantadosi, CA
MLA Citation
Suliman, HB, Welty-Wolf, KE, Carraway, M, Tatro, L, and Piantadosi, CA. "Lipopolysaccharide induces oxidative cardiac mitochondrial damage and biogenesis." Cardiovasc Res 64.2 (November 1, 2004): 279-288.
PMID
15485687
Source
pubmed
Published In
Cardiovascular Research
Volume
64
Issue
2
Publish Date
2004
Start Page
279
End Page
288
DOI
10.1016/j.cardiores.2004.07.005

Discordant extracellular superoxide dismutase expression and activity in neonatal hyperoxic lung.

Antioxidant defenses in the neonatal lung are required to adapt to the oxygen (O(2))-rich postnatal environment, and oxidant/antioxidant imbalance is a predisposition to lung injury when high concentrations of inspired O(2) are used in neonatal lung diseases. The lung's main extracellular enzymatic defense against superoxide, extracellular superoxide dismutase (EC-SOD), is closely regulated during development. In testing the hypothesis that developmental change in EC-SOD expression and activity in the immature lung would be disrupted by hyperoxia, we found a doubling of lung EC-SOD protein in newborn rats exposed to 95% O(2) for 1 week. Furthermore, EC-SOD protein secretion increased, but EC-SOD enzyme activity did not change with O(2) exposure. EC-SOD mRNA did not change at multiple points between 6 hours and 8 days. Lung EC-SOD recovered by immunoprecipitation after 1 week of O(2) showed strong increases in protein nitrotyrosine and variable, nonsignificant differences in protein carbonyl content. These data provide the first direct evidence that EC-SOD is itself a target of nitration in hyperoxia, and offer a plausible explanation for low EC-SOD activity despite its increased secretion by O(2)-exposed neonatal lung.

Authors
Mamo, LB; Suliman, HB; Giles, B-L; Auten, RL; Piantadosi, CA; Nozik-Grayck, E
MLA Citation
Mamo, LB, Suliman, HB, Giles, B-L, Auten, RL, Piantadosi, CA, and Nozik-Grayck, E. "Discordant extracellular superoxide dismutase expression and activity in neonatal hyperoxic lung." Am J Respir Crit Care Med 170.3 (August 1, 2004): 313-318.
PMID
15117745
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
170
Issue
3
Publish Date
2004
Start Page
313
End Page
318
DOI
10.1164/rccm.200309-1282OC

Superoxide dismutase-3 promotes full expression of the EPO response to hypoxia.

Extracellular superoxide dismutase (SOD3) is the primary extracellular enzymatic scavenger of superoxide ((.)O(2)(-)). SOD3's expression is highest in the kidney, but its distribution and biologic functions there are unknown. To investigate the function of renal SOD3, we colocalized it with erythropoietin (EPO) to proximal tubules using in situ hybridization and immunohistochemistry. We then exposed wild-type (Wt) and SOD3 knock-out (KO) mice to hypoxia and found a late hematocrit response in the KO strain. EPO mRNA expression was attenuated in KO mice during the first 6 hours of hypoxia preceded at 2 hours by less accumulation of nuclear hypoxia-inducible transcription factor 1 alpha (HIF-1 alpha) protein. Meanwhile KO mice exposed to hypoxia showed increases in renal mRNA for superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4) and early significant increases in glutathione disulfide (GSSG)/glutathione (GSH), a marker of oxidative stress, compared with Wt mice. Plasma nitrite/nitrate and renal 3-nitrotyrosine (3-NTyr), indicating peroxynitrite formation, increased later in hypoxia, and renal endothelial nitric oxide synthase protein induction was similar in both strains. These data show that hypoxic activation of HIF-1 alpha and its target gene EPO in mouse kidney is regulated closely by the oxidant/antioxidant equilibrium involving SOD3, thus identifying renal SOD3 as a regulatory element in the body's innate adaptation to hypoxia.

Authors
Suliman, HB; Ali, M; Piantadosi, CA
MLA Citation
Suliman, HB, Ali, M, and Piantadosi, CA. "Superoxide dismutase-3 promotes full expression of the EPO response to hypoxia." Blood 104.1 (July 1, 2004): 43-50.
PMID
15016652
Source
pubmed
Published In
Blood
Volume
104
Issue
1
Publish Date
2004
Start Page
43
End Page
50
DOI
10.1182/blood-2003-07-2240

Superoxide dismutase responds to hyperoxia in rat hippocampus.

The brain's anti-oxidant response to highly elevated oxygen (O2) partial pressures is poorly understood. In this study we hypothesized that hyperbaric O2 (HBO2) would stimulate superoxide dismutase (SOD) transcription in the oxidative stress-sensitive rat hippocampus and measured the time course and extent of the changes in hippocampal mRNA for all three SOD isoforms and total SOD enzyme activity. Comparisons were made between exposures to 2 hours of 1 atmosphere pressure normobaric oxygen (NBO); 2 hours of 3 atmospheres HBO2; and room air. Hyperoxia (HBO2 > NBO) was associated with statistically significant increases in transcript levels of the antioxidant enzymes SOD2 (MnSOD) and SOD3 (EC-SOD) at 6 and 18 hours but not SOD1 (Cu, Zn SOD) respectively. Hyperoxia, however, did not affect total hippocampal SOD activity measured at 6 and 24 hours, indicating that the mRNA responses were necessary to maintain the anti-oxidant enzyme activity after oxidative stress.

Authors
Freiberger, J; Coulombe, K; Suliman, H; Carraway, M; Piantadosi, C
MLA Citation
Freiberger, J, Coulombe, K, Suliman, H, Carraway, M, and Piantadosi, C. "Superoxide dismutase responds to hyperoxia in rat hippocampus." Undersea Hyperb Med 31.2 (2004): 227-232.
PMID
15485085
Source
pubmed
Published In
Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc
Volume
31
Issue
2
Publish Date
2004
Start Page
227
End Page
232

Oxidative damage of mitochondria and mitochondrial DNA in sepsis

Authors
Piantadosi, CA; Carraway, MS; Welty-Wolf, KE; Suliman, HB
MLA Citation
Piantadosi, CA, Carraway, MS, Welty-Wolf, KE, and Suliman, HB. "Oxidative damage of mitochondria and mitochondrial DNA in sepsis." 2004.
Source
wos-lite
Published In
Shock
Volume
21
Publish Date
2004
Start Page
57
End Page
57

Lipopolysaccharide stimulates mitochondrial biogenesis via activation of nuclear respiratory factor-1.

Exposure to bacterial lipopolysaccharide (LPS) in vivo damages mitochondrial DNA (mtDNA) and interferes with mitochondrial transcription and oxidative phosphorylation (OXPHOS). Because this damage accompanies oxidative stress and is reversible, we postulated that LPS stimulates mtDNA replication and mitochondrial biogenesis via expression of factors responsive to reactive oxygen species, i.e. nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor-A. In testing this hypothesis in rat liver, we found that LPS induces NRF-1 protein expression and activity accompanied by mRNA expression for mitochondrial transcription factor-A, mtDNA polymerase gamma, NRF-2, and single-stranded DNA-binding protein. These events restored the loss in mtDNA copy number and OXPHOS gene expression caused by LPS and increased hepatocyte mitotic index, nuclear cyclin D1 translocation, and phosphorylation of pro-survival kinase, Akt. Thus, NRF-1 was implicated in oxidant-mediated mitochondrial biogenesis to provide OXPHOS for proliferation. This implication was tested in novel mtDNA-deficient cells generated from rat hepatoma cells that overexpress NRF-1. Depletion of mtDNA (rhoo clones) diminished oxidant production and caused loss of NRF-1 expression and growth delay. NRF-1 expression and growth were restored by exogenous oxidant exposure indicating that oxidative stress stimulates biogenesis in part via NRF-1 activation and corresponding to recovery events after LPS-induced liver damage.

Authors
Suliman, HB; Carraway, MS; Welty-Wolf, KE; Whorton, AR; Piantadosi, CA
MLA Citation
Suliman, HB, Carraway, MS, Welty-Wolf, KE, Whorton, AR, and Piantadosi, CA. "Lipopolysaccharide stimulates mitochondrial biogenesis via activation of nuclear respiratory factor-1." J Biol Chem 278.42 (October 17, 2003): 41510-41518.
PMID
12902348
Source
pubmed
Published In
The Journal of biological chemistry
Volume
278
Issue
42
Publish Date
2003
Start Page
41510
End Page
41518
DOI
10.1074/jbc.M304719200

Postlipopolysaccharide oxidative damage of mitochondrial DNA.

Selected structural and functional alterations of mitochondria induced by bacterial lipopolysaccharide (LPS) were investigated on the basis of the hypothesis that LPS initiates hepatic mitochondrial DNA (mtDNA) damage by oxidative mechanisms. After a single intraperitoneal injection of Escherichia coli LPS, liver mtDNA copy number decreased, as determined by Southern analysis, within 24 hours relative to nuclear 18S rRNA (p < 0.05). LPS induced a novel oxidant-dependent 3.8-kb mtDNA deletion in the region encoding NADH dehydrogenase subunits 1 and 2 and cytochrome c oxidase subunit I, which correlated with mitochondrial glutathione depletion. Expression of mitochondrial mRNA and transcription of mitochondrial RNA were suppressed, whereas mRNA expression increased for selected nuclear-encoded mitochondrial proteins. Resolution of mtDNA damage was mediated by importation of mitochondrial transcription factor A protein, a central regulator of mtDNA copy number, accompanied by binding of mitochondrial protein extract to the mitochondrial transcription factor A DNA-binding site. Hence, mtDNA integrity and transcriptional capacity after LPS administration appeared to be reinstated by mitochondrial biogenesis. These data provide the first link between LPS-mediated hepatic injury and a specific oxidative mtDNA deletion, which inhibits mitochondrial transcription and is restored by activation of mechanisms that lead to biogenesis.

Authors
Suliman, HB; Carraway, MS; Piantadosi, CA
MLA Citation
Suliman, HB, Carraway, MS, and Piantadosi, CA. "Postlipopolysaccharide oxidative damage of mitochondrial DNA." Am J Respir Crit Care Med 167.4 (February 15, 2003): 570-579.
PMID
12480607
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
167
Issue
4
Publish Date
2003
Start Page
570
End Page
579
DOI
10.1164/rccm.200206-518OC

Extracellular superoxide dismutase protects lung development in hyperoxia-exposed newborn mice.

We tested the hypothesis that targeted transgenic overexpression of human extracellular superoxide dismutase (EC-SOD) would preserve alveolar development in hyperoxia-exposed newborn mice. We exposed newborn transgenic and wild-type mice to 95% oxygen (O2) or air x 7 days and measured bronchoalveolar lavage cell counts, and lung homogenate EC-SOD, oxidized and reduced glutathione, and myeloperoxidase. We found that total EC-SOD activity in transgenic newborn mice was approximately 2.5x the wild-type activity. Hyperoxia-exposed transgenic mice had less pulmonary neutrophil influx and oxidized glutathione than wild-type littermates at 7 days. We measured alveolar surface and volume density in animals exposed to 14 days more of air or 60% O2. Hyperoxia-exposed transgenic EC-SOD mice had significant preservation of alveolar surface and volume density compared with wild-type littermates. After 7 days 95% O2 + 14 days 60% O2, lung inflammation measured as myeloperoxidase activity was reduced to control levels in all treatment groups.

Authors
Ahmed, MN; Suliman, HB; Folz, RJ; Nozik-Grayck, E; Golson, ML; Mason, SN; Auten, RL
MLA Citation
Ahmed, MN, Suliman, HB, Folz, RJ, Nozik-Grayck, E, Golson, ML, Mason, SN, and Auten, RL. "Extracellular superoxide dismutase protects lung development in hyperoxia-exposed newborn mice." Am J Respir Crit Care Med 167.3 (February 1, 2003): 400-405.
PMID
12406846
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
167
Issue
3
Publish Date
2003
Start Page
400
End Page
405
DOI
10.1164/rccm.200202-108OC

Testicular germ-cell apoptosis in stressed rats following combined exposure to pyridostigmine bromide, N,N-diethyl m-toluamide (DEET), and permethrin.

This study reports and characterizes the testicular apoptosis following daily exposure of male Sprague-Dawley rats to subchronic combined doses of pyridostigmine bromide (PB, 1.3 mg/kg/d in water, oral), a drug used for treatment of myasthenia gravis and prophylactic treatment against nerve agents during the Persian Gulf War; the insect repellent N,N-diethyl m-toluamide (DEET, 40 mg/kg/d in ethanol, dermal); and the insecticide permethrin (0.13 mg/kg in ethanol, dermal), with and without stress for 28 d. Combined exposure to these chemicals was implicated in the development of illnesses including genitourinary disorders among many veterans of the Persian Gulf War. Previous studies from this laboratory have shown that exposure to combination of these chemicals produced greater toxicity compared to single components. Exposure to stress alone did not cause any significant histopathological alterations in the testes. Administration of combination of these chemicals induced apoptosis in rat testicular germ cells, Sertoli cells, and Leydig cells, as well as in the endothelial lining of the blood vessels. Testicular damage was significantly augmented when the animals were further exposed to a combination of chemicals and stress. Histopathological examination of testicular tissue sections showed that apoptosis was confined to the basal germ cells and spermatocytes, indicating suppression of spermatogenesis. Increased apoptosis of testicular cells coincided, in timing and localization, with increased expression of the apoptosis-promoting proteins Bax and p53. Furthermore, significant increase of 3-nitrotyrosine immunostaining in the testis revealed oxidative and/or nitrosation induction of cell death. In conclusion, combined exposure to real-life doses of test compounds caused germ-cell apoptosis that was significantly enhanced by stress.

Authors
Abou-Donia, MB; Suliman, HB; Khan, WA; Abdel-Rahman, AA
MLA Citation
Abou-Donia, MB, Suliman, HB, Khan, WA, and Abdel-Rahman, AA. "Testicular germ-cell apoptosis in stressed rats following combined exposure to pyridostigmine bromide, N,N-diethyl m-toluamide (DEET), and permethrin." J Toxicol Environ Health A 66.1 (January 10, 2003): 57-73.
PMID
12587291
Source
pubmed
Published In
Journal of Toxicology & Environmental Health: Part A
Volume
66
Issue
1
Publish Date
2003
Start Page
57
End Page
73
DOI
10.1080/15287390306463

Testicular germ-cell apoptosis in stressed rats following combined exposure to pyridostigmine bromide, N,N-diethyl m-toluamide (DEET), and permethrin

Authors
Abou-Donia, MB; Suliman, HB; Khan, WA; Abdel-Rahman, AA
MLA Citation
Abou-Donia, MB, Suliman, HB, Khan, WA, and Abdel-Rahman, AA. "Testicular germ-cell apoptosis in stressed rats following combined exposure to pyridostigmine bromide, N,N-diethyl m-toluamide (DEET), and permethrin." JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A 66.1 (January 10, 2003): 57-73.
Source
wos-lite
Published In
Journal of Toxicology & Environmental Health: Part A
Volume
66
Issue
1
Publish Date
2003
Start Page
57
End Page
73
DOI
10.1080/15287390390155750

Postlipopolysaccharide oxidative damage of mitochondrial DNA

Authors
SULIMAN, H
MLA Citation
SULIMAN, H. "Postlipopolysaccharide oxidative damage of mitochondrial DNA." Am J Respir Crit Care Med 167 (2003): 570-579.
Source
cinii-english
Published In
Am J Respir Crit Care Med
Volume
167
Publish Date
2003
Start Page
570
End Page
579
DOI
10.1164/rccm.200206-518OC

Overexpression of extracellular superoxide dismutase decreases lung injury after exposure to oil fly ash.

The mechanism of tissue injury after exposure to air pollution particles is not known. The biological effect has been postulated to be mediated via an oxidative stress catalyzed by metals present in particulate matter (PM). We utilized a transgenic (Tg) mouse model that overexpresses extracellular superoxide dismutase (EC-SOD) to test the hypothesis that lung injury after exposure to PM results from an oxidative stress in the lower respiratory tract. Wild-type (Wt) and Tg mice were intratracheally instilled with either saline or 50 microg of residual oil fly ash (ROFA). Twenty-four hours later, specimens were obtained and included bronchoalveolar lavage (BAL) and lung for both homogenization and light histopathology. After ROFA exposure, EC-SOD Tg mice showed a significant reduction in BAL total cell counts (composed primarily of neutrophils) and BAL total protein compared with Wt. EC-SOD animals also demonstrated diminished concentrations of inflammatory mediators in BAL. There was no statistically significant difference in BAL lipid peroxidation; however, EC-SOD mice had lower concentrations of oxidized glutathione in the BAL. We conclude that enhanced EC-SOD expression decreased both lung inflammation and damage after exposure to ROFA. This supports a participation of oxidative stress in the inflammatory injury after PM exposure rather than reflecting a response to metals alone.

Authors
Ghio, AJ; Suliman, HB; Carter, JD; Abushamaa, AM; Folz, RJ
MLA Citation
Ghio, AJ, Suliman, HB, Carter, JD, Abushamaa, AM, and Folz, RJ. "Overexpression of extracellular superoxide dismutase decreases lung injury after exposure to oil fly ash." Am J Physiol Lung Cell Mol Physiol 283.1 (July 2002): L211-L218.
PMID
12060579
Source
pubmed
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
283
Issue
1
Publish Date
2002
Start Page
L211
End Page
L218
DOI
10.1152/ajplung.00409.2001

Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine release after intratracheal lipopolysaccharide.

Initiation of coagulation by tissue factor (TF) is a potentially powerful regulator of local inflammatory responses. We hypothesized that blockade of TF-factor VIIa (FVIIa) complex would decrease lung inflammation and proinflammatory cytokine release after tracheal instillation of Escherichia coli lipopolysaccharide (LPS 0111:B4). At the time of injury, rats received one dose of site-inactivated FVIIa (FFR-FVIIa) or saline intravenously. At 0, 6,12, 24, and 48 h after injury, lungs were examined for histologic changes and bronchoalveolar lavage (BAL) was performed to assess protein, lactate dehydrogenase (LDH) activity, cell counts, and cytokine levels. LPS-injured rats treated with FFR-FVIIa showed decreased intra-alveolar inflammation and fibrin deposition by light microscopy compared with untreated rats. This was accompanied by decreased protein leakage (P < 0.0001), LDH activity (P < 0.0001), and local elaboration of interleukin (IL)-1beta, IL-6, and IL-10 (all P < 0.0001), but not tumor necrosis factor (TNF)-alpha. Protection was associated with reduction of TF mRNA expression in whole lung, but not with changes in nuclear translocation of nuclear factor (NF)-kappaB. FFR-FVIIa given 6 h after LPS afforded equivalent lung protection. Therefore, blockade of TF-FVIIa complex protects the lung from injury by LPS in part by reducing local expression of proinflammatory cytokines and may offer promise for therapy of acute lung injury.

Authors
Miller, DL; Welty-Wolf, K; Carraway, MS; Ezban, M; Ghio, A; Suliman, H; Piantadosi, CA
MLA Citation
Miller, DL, Welty-Wolf, K, Carraway, MS, Ezban, M, Ghio, A, Suliman, H, and Piantadosi, CA. "Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine release after intratracheal lipopolysaccharide." Am J Respir Cell Mol Biol 26.6 (June 2002): 650-658.
PMID
12034563
Source
pubmed
Published In
American journal of respiratory cell and molecular biology
Volume
26
Issue
6
Publish Date
2002
Start Page
650
End Page
658
DOI
10.1165/ajrcmb.26.6.4688

Early differential elevation and persistence of phosphorylated cAMP-response element binding protein (p-CREB) in the central nervous system of hens treated with diisopropyl phosphorofluoridate, an OPIDN-causing compound.

Diisopropyl phosphorofluoridate (DFP) produces organophosphorus-ester-induced delayed neurotoxicity in sensitive species. We studied the effect of single dose of DFP on the expression of phosphorylated cAMP-response element binding protein (p-CREB), which is a well known transcription factor involved in several pathways mediating different types of external stimuli. The hens were perfused with neutral buffered formalin at different time points, i.e., 0.5, 1.0, and 2.0 hrs, as well as 1, 2, 5, and 20 days after dosing. The central nervous system regions of the whole brain were dissected and 7-micron sections were stained for either p-CREB immunopositivity or with hematoxylin and eosin. Results indicated an early differential increase of p-CREB immunopositivity in susceptible regions such as cerebellum, brainstem, and midbrain within 2 hrs. These induced levels persisted upto 5 days in these tissues, although the time course of p-CREB immunopositivity was distinctly different for each region. In the cerebellum induction of p-CREB was seen in the granular layer where both the granulocytes and the glial cells showed induction. Increased immunopositivity for p-CREB in the Purkinje cells and in some basket cells of the molecular layer was noticed over time, but the induction was not as great as in the granular layer. Of all the tissues cerebellum showed the strongest intensity of immunopositivity of the cells as well as the highest (absolute) number of pCREB-positive cells. The brainstem showed a similar fluctuating pattern like the cerebellum with the highest percentage increase of the immunoreactive cells at 5 days preceded by the lowest dip in immunopositivity at 2 days. In the midbrain, there was a time-dependent increase in the immunopositivity from 0.5 hr onwards until reaching control levels at 20 days. Immunopositivity was also noted in portions of the spina medularis and spina oblongata. The cerebrum (non-susceptible tissue) of DFP-treated hens did not show much deviation from the controls. The endothelial cells of the susceptible regions showed induction at early time points, in contrast to the absence of induction in cerebrum. Spatial and temporal differences in the immunopositivity pattern indicate probable involvement of CREB-independent pathways also. Overall, the complex induction pattern of p-CREB, along with our earlier observations of the early induction of c-fos, c-jun and Protein Kinase A (PKA) as well as the induction of Calcium2+/Calmodulin dependent Protein Kinase II (CaM kinase II) at later periods, strongly suggest an activator role of CREB mediated pathways that may lead to the clinical development of delayed neurotoxicity.

Authors
Damodaran, TV; Abdel-Rahman, AA; Suliman, HB; Abou-Donia, MB
MLA Citation
Damodaran, TV, Abdel-Rahman, AA, Suliman, HB, and Abou-Donia, MB. "Early differential elevation and persistence of phosphorylated cAMP-response element binding protein (p-CREB) in the central nervous system of hens treated with diisopropyl phosphorofluoridate, an OPIDN-causing compound." Neurochem Res 27.3 (March 2002): 183-193.
PMID
11958515
Source
pubmed
Published In
Neurochemical Research
Volume
27
Issue
3
Publish Date
2002
Start Page
183
End Page
193

Rapid mtDNA deletion by oxidants in rat liver mitochondria after hemin exposure.

The amounts of superoxide and hydrogen peroxide generated by mitochondria under physiological conditions can be enhanced by cellular stress. This study tested the hypothesis that the response to hemin-induced stress, which includes heme oxygenase-1 (HO-1) induction, predisposes to oxidative damage of mitochondrial DNA (mtDNA). Hepatic mitochondria from control, hemin-, and CO-exposed rats were incubated with tert-butyl hydroperoxide (tert-BH) or the NO donor 1,2,3,4-oxatriazolium, 5-amino-3- (3,4-dichlorophenyl)-chloride (GEA 3162). Mitochondrial total and oxidized glutathione (GSH and GSSG), total and free iron, and 8-oxo-7, 8-dihydro-2' deoxyguanosine (8-OHdG) were determined with and without oxidants. As expected, oxidation by tert-BH induced significant GSH depletion and increased amounts of free iron and 8-OhdG. Oxidant exposure rapidly produced a large mtDNA deletion involving the coding regions for cytochrome c oxidase (COX 1) and NADH dehydrogenase (ND1 and ND2). Hemin and CO greatly exacerbated susceptibility to the deletion of mtDNA by tert-BH, and this was attenuated by preincubation with GSH methyl ester. Analysis of mitochondria-associated proteins Bax and Bcl-xl in hemin- and CO-exposed rats showed significant responses, revealing interactions with apoptotic pathways. Thus, hemin-induced mitochondrial events sensitize a specific region of the mitochondrial genome to deletion, which is related to depletion of GSH and is not explained by effects of CO. This mtDNA damage is associated with altered expression of mitochondrial cell death proteins, thereby suggesting a novel mechanism for systemic or environmental pro-oxidants to influence apoptosis.

Authors
Suliman, HB; Carraway, MS; Velsor, LW; Day, BJ; Ghio, AJ; Piantadosi, CA
MLA Citation
Suliman, HB, Carraway, MS, Velsor, LW, Day, BJ, Ghio, AJ, and Piantadosi, CA. "Rapid mtDNA deletion by oxidants in rat liver mitochondria after hemin exposure." Free Radic Biol Med 32.3 (February 1, 2002): 246-256.
PMID
11827750
Source
pubmed
Published In
Free Radical Biology & Medicine
Volume
32
Issue
3
Publish Date
2002
Start Page
246
End Page
256

Prenatal hypoxia decreases lung extracellular superoxide dismutase expression and activity

Extracellular superoxide dismutase (EC-SOD), which scavenges extracellular superoxide (O2-·), is highly regulated in the developing lung. In the prenatal rabbit, EC-SOD is predominantly intracellular and inactive, and postnatally, active EC-SOD is secreted. We hypothesized that prenatal hypoxia would delay the normal postnatal secretion of active EC-SOD in the lung. Pregnant New Zealand White rabbits were exposed to hypobaric hypoxia (15,000 ft × 36 h) to alter fetal O2 tension or were maintained in room air. Lungs were harvested from preterm (28 days), term (30 ± 1 day), and 1-wk-old kits. After prenatal hypobaric hypoxia, EC-SOD mRNA expression was significantly decreased in lungs of full-term kits, whereas EC-SOD protein decreased at all ages. Immunohistochemical staining for EC-SOD showed that hypoxia delayed secretion of the isoenzyme in the airways and pulmonary vasculature. Furthermore, pulmonary EC-SOD enzyme activity was significantly decreased in the 1-wk-old kits exposed to prenatal hypoxia. We conclude that prenatal hypoxia downregulates EC-SOD expression at both the transcriptional and posttranslational levels. Furthermore, prenatal hypoxia delays secretion of active EC-SOD enzyme. These findings have important implications for the effects of prenatal asphyxia on postnatal response to oxidant stress.

Authors
Giles, B-L; Suliman, H; Mamo, LB; Piantadosi, CA; Oury, TD; Nozik-Grayck, E
MLA Citation
Giles, B-L, Suliman, H, Mamo, LB, Piantadosi, CA, Oury, TD, and Nozik-Grayck, E. "Prenatal hypoxia decreases lung extracellular superoxide dismutase expression and activity." American Journal of Physiology - Lung Cellular and Molecular Physiology 283.3 27-3 (2002): L549-L554.
Source
scival
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
283
Issue
3 27-3
Publish Date
2002
Start Page
L549
End Page
L554

Carbon monoxide promotes hypoxic pulmonary vascular remodeling

CO is a biologically active gas that produces cellular effects by multiple mechanisms. Because cellular binding of CO by heme proteins is increased in hypoxia, we tested the hypothesis that CO interferes with hypoxic pulmonary vascular remodeling in vivo. Rats were exposed to inspired CO (50 parts/ million) at sea level or 18,000 ft of altitude [hypobaric hypoxia (HH)], and changes in vessel morphometry and pulmonary pressure-flow relationships were compared with controls. Vascular cell single strand DNA (ssDNA) and proliferating cell nuclear antigen (PCNA) were assessed, and changes in gene and protein expression of smooth muscle α-actin (sm-αactin), β-actin, and heme oxygenase-1 (HO-1) were evaluated by Western analysis, RT-PCR, and immunohistochemistry. After 21 days of HH, vascular pressure at constant flow and vessel wall thickness increased and lumen diameter of small arteries decreased significantly. The presence of CO, however, further increased both pulmonary vascular resistance (PVR) and the number of small muscular vessels compared with HH alone. CO + HH also increased vascular PCNA and nuclear ssDNA expression compared with hypoxia, suggesting accelerated cell turnover. CO in hypoxia downregulated sm-αactin and strongly upregulated β-actin. CO also increased lung HO activity and HO-1 mRNA and protein expression in small pulmonary arteries during hypoxia. These data indicate an overall propensity of CO in HH to promote vascular remodeling and increase PVR in vivo.

Authors
Carraway, MS; Ghio, AJ; Suliman, HB; Carter, JD; Whorton, AR; Piantadosi, CA
MLA Citation
Carraway, MS, Ghio, AJ, Suliman, HB, Carter, JD, Whorton, AR, and Piantadosi, CA. "Carbon monoxide promotes hypoxic pulmonary vascular remodeling." American Journal of Physiology - Lung Cellular and Molecular Physiology 282.4 26-4 (2002): L693-L702.
Source
scival
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
282
Issue
4 26-4
Publish Date
2002
Start Page
L693
End Page
L702

Overexpression of extracellular superoxide dismutase decreases lung injury after exposure to oil fly ash

The mechanism of tissue injury after exposure to air pollution particles is not known. The biological effect has been postulated to be mediated via an oxidative stress catalyzed by metals present in particulate matter (PM). We utilized a transgenic (Tg) mouse model that overexpresses extracellular superoxide dismutase (EC-SOD) to test the hypothesis that lung injury after exposure to PM results from an oxidative stress in the lower respiratory tract. Wild-type (Wt) and Tg mice were intratracheally instilled with either saline or 50 μg of residual oil fly ash (ROFA). Twenty-four hours later, specimens were obtained and included bronchoalveolar lavage (BAL) and lung for both homogenization and light histopathology. After ROFA exposure, EC-SOD Tg mice showed a significant reduction in BAL total cell counts (composed primarily of neutrophils) and BAL total protein compared with Wt. ECSOD animals also demonstrated diminished concentrations of inflammatory mediators in BAL. There was no statistically significant difference in BAL lipid peroxidation; however, EC-SOD mice had lower concentrations of oxidized glutathione in the BAL. We conclude that enhanced EC-SOD expression decreased both lung inflammation and damage after exposure to ROFA. This supports a participation of oxidative stress in the inflammatory injury after PM exposure rather than reflecting a response to metals alone.

Authors
Ghio, AJ; Suliman, HB; Carter, JD; Abushamaa, AM; Folz, RJ
MLA Citation
Ghio, AJ, Suliman, HB, Carter, JD, Abushamaa, AM, and Folz, RJ. "Overexpression of extracellular superoxide dismutase decreases lung injury after exposure to oil fly ash." American Journal of Physiology - Lung Cellular and Molecular Physiology 283.1 27-1 (2002): L211-L218.
Source
scival
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
283
Issue
1 27-1
Publish Date
2002
Start Page
L211
End Page
L218

Induction of urinary excretion of 3-nitrotyrosine, a marker of oxidative stress, following administration of pyridostigmine bromide, DEET (N,N-diethyl-m-toluamide) and permethrin, alone and in combination in rats.

In this study, we determined levels of 3-nitrotyrosine in rat urine following administration of a single oral dose of 13 mg/kg pyridostigmine bromide (PB) (3-dimethylaminocarbonyloxy-N-methylpyridinum bromide), a single dermal dose of 400 mg/kg N,N-diethyl-m-toluamide (DEET) and a single dermal dose of 1.3 mg/kg permethrin, alone and in combination. Urine samples were collected from five treated and five control rats at 4, 8, 16, 24, 48, and 72 h following dosing. Solid-phase extraction coupled with high-performance liquid chromatography with ultraviolet detection at 274 nm was used for the determination of tyrosine and 3-nitrotyrosine. A single oral dose of PB and a single dermal dose of DEET or their combination significantly (P<0.05) increased levels of 3-nitrotyrosine starting 24 h after dosing compared with control urine samples. The maximum increase of 3-nitroytyrosine was detected 48 h after combined administration of PB and DEET. The ratio of 3-nitrotyrosine to tyrosine in urine excreted 48 h after dosing was 0.19+/-0.04, 0.20+/-0.05, 0.28+/-0.03, 0.32+/-0.04, 0.19+/-0.05, 0.42+/-0.04, 0.27+/-0.03, 0.36+/-0.04, and 0.48+/-0.04 following administration of water, ethanol, PB, DEET, permethrin, PB+DEET, PB+permethrin, DEET+permethrin, and PB+DEET+permethrin, respectively. The results indicate that an oral dose of PB and a dermal administration of DEET, alone and in combination, could generate free radical species, and thus increase levels of 3-nitrotyrosine in rat urine. Induction of 3-nitrotyrosine, a marker of oxidative stress, following exposure to these compounds could be significant in understanding the proposed enhanced toxicity following combined exposure to these compounds.

Authors
Abu-Qare, AW; Suliman, HB; Abou-Donia, MB
MLA Citation
Abu-Qare, AW, Suliman, HB, and Abou-Donia, MB. "Induction of urinary excretion of 3-nitrotyrosine, a marker of oxidative stress, following administration of pyridostigmine bromide, DEET (N,N-diethyl-m-toluamide) and permethrin, alone and in combination in rats." Toxicol Lett 121.2 (April 30, 2001): 127-134.
PMID
11325563
Source
pubmed
Published In
Toxicology Letters
Volume
121
Issue
2
Publish Date
2001
Start Page
127
End Page
134

Inhaled carbon monoxide and hyperoxic lung injury in rats

Because carbon monoxide (CO) has been proposed to have anti-inflammatory properties, we sought protective effects of CO in pulmonary O2 toxicity, which leads rapidly to lung inflammation and respiratory failure. Based on published studies, we hypothesized that CO protects the lung against O2 by selectively increasing expression of antioxidant enzymes, thereby decreasing oxidative injury and inflammation. Rats exposed to O2 with or without CO [50-500 parts/million (ppm)] for 60 h were compared for lung wet-to-dry weight ratio (W/D), pleural fluid volume, myeloperoxidase (MPO) activity, histology, expression of heme oxygenase-1 (HO-1), and manganese superoxide dismutase (Mn SOD) proteins. The brains were evaluated for histological evidence of damage from CO. In O2-exposed animals, lung W/D increased from 4.8 in normal rats to 6.3; however, only CO at 200 and 500 ppm decreased W/D significantly (to 5.9) during O2 exposure. Large volumes of pleural fluid accumulated in all rats, with no significant CO treatment effect. Lung MPO values increased after O2 and were not attenuated by CO treatment. CO did not enhance lung expression of oxidant-responsive proteins Mn SOD and HO-1. Animals receiving O2 and CO at 200 or 500 ppm showed significant apoptotic cell death in the cortex and hippocampus by immunochemical staining. Thus significant protection by CO against O2-induced lung injury could not be confirmed in rats, even at CO concentrations associated with apoptosis in the brain.

Authors
Clayton, CE; Carraway, MS; Suliman, HB; Thalmann, ED; Thalmann, KN; Schmechel, DE; Piantadosi, CA
MLA Citation
Clayton, CE, Carraway, MS, Suliman, HB, Thalmann, ED, Thalmann, KN, Schmechel, DE, and Piantadosi, CA. "Inhaled carbon monoxide and hyperoxic lung injury in rats." American Journal of Physiology - Lung Cellular and Molecular Physiology 281.4 25-4 (2001): L949-L957.
Source
scival
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
281
Issue
4 25-4
Publish Date
2001
Start Page
L949
End Page
L957

Prevention of influenza-induced lung injury in mice overexpressing extracellular superoxide dismutase

Reactive oxygen and nitrogen species such as superoxide and nitric oxide are released into the extracellular spaces by inflammatory and airway epithelial cells. These molecules may exacerbate lung injury after influenza virus pneumonia. We hypothesized that enhanced expression of extracellular superoxide dismutase (EC SOD) in mouse airways would attenuate the pathological effects of influenza pneumonia. We compared the pathogenic effects of a nonlethal primary infection with mouse-adapted Hong Kong influenza A/68 virus in transgenic (TG) EC SOD mice versus non-TG (wild-type) littermates. Compared with wild-type mice, EC SOD TG mice showed less lung injury and inflammation as measured by significant blunting of interferon-γ induction, reduced cell count and total protein in bronchoalveolar lavage fluid, reduced levels of lung nitrite/nitrate nitrotyrosine, and markedly reduced lung pathology. These results demonstrate that enhancing EC SOD in the conducting and distal airways of the lung minimizes influenza-induced lung injury by both ameliorating inflammation and attenuating oxidative stress.

Authors
Suliman, HB; Ryan, LK; Bishop, L; Folz, RJ
MLA Citation
Suliman, HB, Ryan, LK, Bishop, L, and Folz, RJ. "Prevention of influenza-induced lung injury in mice overexpressing extracellular superoxide dismutase." American Journal of Physiology - Lung Cellular and Molecular Physiology 280.1 24-1 (2001): L69-L78.
Source
scival
Published In
American Journal of Physiology - Lung Cellular and Molecular Physiology
Volume
280
Issue
1 24-1
Publish Date
2001
Start Page
L69
End Page
L78

Differential localization of placental extracellular superoxide dismutase as pregnancy progresses.

OBJECTIVE: The aim of this study was to determine placental localization and activity of extracellular superoxide dismutase, a nitric oxide modulator, during early gestation and to correlate these characteristics with fetal vascular development. STUDY DESIGN: First-trimester (n = 10) and second-trimester (n = 10) villi were obtained at elective pregnancy termination. Extracellular superoxide dismutase was localized by means of an immunoperoxidase method. Activity was measured by determining the inhibition of cytochrome c reduction at pH 10 and messenger ribonucleic acid expression by in situ hybridization. RESULTS: Extracellular superoxide dismutase was intracellular within villous trophoblasts until 17 weeks' gestation, when it relocated to the villous extracellular matrix. Activities were similar between first- and second-trimester villi. In situ hybridization confirmed extracellular superoxide dismutase messenger ribonucleic acid within trophoblasts throughout gestation. CONCLUSION: Extracellular superoxide dismutase is produced by trophoblasts early in pregnancy, but it remains intracellular until 17 weeks' gestation, which may be related to fetal vascular development.

Authors
Boggess, KA; Kay, HH; Crapo, JD; Moore, WF; Suliman, HB; Oury, TD
MLA Citation
Boggess, KA, Kay, HH, Crapo, JD, Moore, WF, Suliman, HB, and Oury, TD. "Differential localization of placental extracellular superoxide dismutase as pregnancy progresses." Am J Obstet Gynecol 183.1 (July 2000): 199-205.
PMID
10920331
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
183
Issue
1
Publish Date
2000
Start Page
199
End Page
205
DOI
10.1067/mob.2000.105426

Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia.

Extracellular superoxide dismutase (EC-SOD, or SOD3) is the major extracellular antioxidant enzyme in the lung. To study the biologic role of EC-SOD in hyperoxic-induced pulmonary disease, we created transgenic (Tg) mice that specifically target overexpression of human EC-SOD (hEC-SOD) to alveolar type II and nonciliated bronchial epithelial cells. Mice heterozygous for the hEC-SOD transgene showed threefold higher EC-SOD levels in the lung compared with wild-type (Wt) littermate controls. A significant amount of hEC-SOD was present in the epithelial lining fluid layer. Both Tg and Wt mice were exposed to normobaric hyperoxia (>99% oxygen) for 48, 72, and 84 hours. Mice overexpressing hEC-SOD in the airways attenuated the hyperoxic lung injury response, showed decreased morphologic evidence of lung damage, had reduced numbers of recruited inflammatory cells, and had a reduced lung wet/dry ratio. To evaluate whether reduced numbers of neutrophil infiltration were directly responsible for the tolerance to oxygen toxicity observed in the Tg mice, we made Wt and Tg mice neutropenic using anti-neutrophil antibodies and subsequently exposed them to 72 hours of hyperoxia. Both Wt and Tg neutrophil-depleted (ND) mice have less severe lung injury compared with non-ND animals, thus providing direct evidence that neutrophils recruited to the lung during hyperoxia play a distinct role in the resultant acute lung injury. We conclude that oxidative and inflammatory processes in the extracellular lung compartment contribute to hyperoxic-induced lung damage and that overexpression of hEC-SOD mediates a protective response to hyperoxia, at least in part, by attenuating the neutrophil inflammatory response.

Authors
Folz, RJ; Abushamaa, AM; Suliman, HB
MLA Citation
Folz, RJ, Abushamaa, AM, and Suliman, HB. "Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia." J Clin Invest 103.7 (April 1999): 1055-1066.
PMID
10194479
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
103
Issue
7
Publish Date
1999
Start Page
1055
End Page
1066
DOI
10.1172/JCI3816

Analysis of erythropoietin and erythropoietin receptor genes expression in cattle during acute infection with Trypanosoma congolense.

Acute Trypanosoma congolense infection induced moderate, transient anemia in N'Dama cattle (trypanotolerant) and severe anemia in Boran cattle (trypanosusceptible). Erythropoietin receptor (EpoR) was cloned and sequenced from the two breeds of cattle. A single position mutation of Tyr in the Boran to His in the N'Dama predicted amino acid sequence was revealed. The mRNA transcription of erythropoietin (Epo) in kidneys and EpoR in the bone marrow of infected cattle was determined by competitive reverse transcription and the polymerase chain reaction (RT-PCR). Though Epo mRNA transcription increased in the kidneys during infection, the increase was not significantly different (p>0.05) between the two breeds of infected cattle. The level of EpoR transcripts in the bone marrow of infected N'Damas was significantly higher (p<0.05) than that detected in the marrows from infected Boran cattle. While infection seem to increase levels of transcription of IL-1alpha and beta, and TNFalpha in kidneys from both Boran and N'Dama cattle, no significant difference was detected in the level of mRNAs of these cytokines in the kidney from the two breed of cattle. The amount of IFNgamma mRNA transcripts were not changed with infection in N'Dama cattle, while on the contrary a significant higher levels of IFNgamma was found in kidneys from infected Boran cattle as compared to the other groups. A significant (p<0.05) increase in the levels of IL-1alpha and beta, and IFNgamma mRNA transcripts were detected in the marrows of infected Borans as compared to the infected N'Dama cattle. In this study the increase in the level of TNFalpha mRNA in the marrows of the two infected breeds was not different. This implies there is no negative effect of TNFalpha on hematopoiesis during acute infection. These findings suggest that the levels of Epo and EpoR in the infected Boran cattle were inadequate for their degree of anemia, which might be due in part to high expression of IFNgamma during acute infection with T. congolense.

Authors
Suliman, HB; Logan-Henfrey, L; Majiwa, PA; ole-Moiyoi, O; Feldman, BF
MLA Citation
Suliman, HB, Logan-Henfrey, L, Majiwa, PA, ole-Moiyoi, O, and Feldman, BF. "Analysis of erythropoietin and erythropoietin receptor genes expression in cattle during acute infection with Trypanosoma congolense." Exp Hematol 27.1 (January 1999): 37-45.
PMID
9923442
Source
pubmed
Published In
Experimental Hematology
Volume
27
Issue
1
Publish Date
1999
Start Page
37
End Page
45

Expression of TGFα in meningiomas

The objective of this study was to examine the expression of transforming growth factor α (TGFα), a mitogen for many cell types, and its receptor in basic subtypes of meningiomas as well as in meningiomas of varying grade. Formalin-fixed tissues from 26 meningiomas including 15 benign (5 meningothelial, 5 transitional, and 5 fibrous variants), 6 atypical, and 5 malignant examples were immunohistochemically examined for both TGFα protein and EGF/TGFα receptor protein. In addition, in situ hybridization (ISH) was used to detect TGFα mRNA expression. Immunostaining for TGFα was strongest in fibrous and atypical meningiomas, followed closely by transitional and malignant tumors. Only weak reactivity was observed in the meningothelial variant. In all but 4 tumors (2 fibrous, 2 atypical), ISH showed TGFα mRNA to be present, the signal being stronger in malignant than in conventional or atypical tumors. Lastly, immunostaining for EGF/TGFα receptor was positive in all tumors studied. Strong TGFα protein expression in meningiomas is commonly associated with fibrous morphology. Although the frequent detection of both TGFα protein and its mRNA, as well as of EGF/TGFα receptor within tumors of all type and grades, suggests that TGFα serves to promote tumor growth, its possible role in tumorigenesis or malignant progression is uncertain. In summary, demonstration of these substances is of no utility in the classification or grading of this common tumor because the differences in their expression among the various meningioma subtypes were not statistically significant.

Authors
Halper, J; Jung, C; Perry, A; Suliman, H; Hill, MP; Scheithauer, B
MLA Citation
Halper, J, Jung, C, Perry, A, Suliman, H, Hill, MP, and Scheithauer, B. "Expression of TGFα in meningiomas." Journal of Neuro-Oncology 45.2 (1999): 127-134.
PMID
10778728
Source
scival
Published In
Journal of Neuro-Oncology
Volume
45
Issue
2
Publish Date
1999
Start Page
127
End Page
134
DOI
10.1023/A:1006365725033

Cloning of a cDNA encoding bovine erythropoietin and analysis of its transcription in selected tissues.

A bovine cDNA encoding erythropoietin (Epo) was isolated by polymerase chain reaction (PCR) amplification and screening of a bovine kidney cDNA library. The sequenced cDNA has a length of 1312 bp and an open reading frame that encodes a predicted 192-amino-acid (aa) protein, including a putative signal sequence of 25 aa. A mature protein of 167 aa (18.4 kDa) results upon cleavage of the putative signal peptide. The deduced bovine mature Epo peptide exhibits 96, 88, 83, 82 and 79% sequence identity to that of sheep, swine, human, monkey and rat, respectively. The expression of the bovine Epo gene in tissues from a severely anemic calf, bovine fetus and a healthy steer was analysed by a competitive RT-PCR method. In kidneys of the severely anemic calf, Epo mRNA levels increased 60-fold relative to that from the kidneys of the healthy steer. Epo mRNA levels were threefold higher in the liver of the bovine fetus than that in its kidneys. Low levels of Epo transcripts were detected in RNA from spleen of the severely anemic calf and the bovine fetus. No Epo transcripts were detectable in spleen from the healthy steer.

Authors
Suliman, HB; Majiwa, PA; Feldman, BF; Mertens, B; Logan-Henfrey, L
MLA Citation
Suliman, HB, Majiwa, PA, Feldman, BF, Mertens, B, and Logan-Henfrey, L. "Cloning of a cDNA encoding bovine erythropoietin and analysis of its transcription in selected tissues." Gene 171.2 (June 1, 1996): 275-280.
PMID
8666286
Source
pubmed
Published In
Gene
Volume
171
Issue
2
Publish Date
1996
Start Page
275
End Page
280

Disseminated intravascular coagulation: Present and future perspective

Authors
Gopegui, RRD; Suliman, HB; Feldman, BF
MLA Citation
Gopegui, RRD, Suliman, HB, and Feldman, BF. "Disseminated intravascular coagulation: Present and future perspective." Comparative Haematology International 5.4 (1995): 213-226.
Source
scival
Published In
Comparative Haematology International
Volume
5
Issue
4
Publish Date
1995
Start Page
213
End Page
226
DOI
10.1007/BF02044138

Prevalence of mastitis in imported Friesian cows in Sudan.

Three hundred twenty-two lactating Friesian cows were examined for mastitis by different diagnostic techniques. The predominant pathogens encountered were Staphylococci, Streptococci, Corynebacterium and Escherichia coli spp.

Authors
Abdelrahim, AI; Shommein, AM; Suliman, HB; Shaddad, SA
MLA Citation
Abdelrahim, AI, Shommein, AM, Suliman, HB, and Shaddad, SA. "Prevalence of mastitis in imported Friesian cows in Sudan." Rev Elev Med Vet Pays Trop 42.4 (1990): 512-514.
PMID
2218036
Source
pubmed
Published In
Revue d'Elevage et de Medecine Veterinaire des Pays Tropicaux
Volume
42
Issue
4
Publish Date
1990
Start Page
512
End Page
514

Zinc deficiency in sheep: field cases.

Zinc deficiency was diagnosed in a sheep farm in Khartoum Province; the young sheep and lambs were mostly affected. Skin lesions, depression, wool eating, flexed knees and a markedly stiff gait were observed. Histopathology of the skin revealed mainly hyperkeratosis accompanied sometimes by parakeratosis. The animals responded rapidly to oral administration of zinc oxide.

Authors
Suliman, HB; Abdelrahim, AI; Zakia, AM; Shommein, AM
MLA Citation
Suliman, HB, Abdelrahim, AI, Zakia, AM, and Shommein, AM. "Zinc deficiency in sheep: field cases." Trop Anim Health Prod 20.1 (February 1988): 47-51.
PMID
3354059
Source
pubmed
Published In
Tropical Animal Health and Production
Volume
20
Issue
1
Publish Date
1988
Start Page
47
End Page
51

Acute mycotoxicosis in sheep: field cases.

Inappetence, apathy and neurological signs were seen in a flock of sheep at an out-station of Khartoum, that were fed on groundnut cake meal contaminated with aflatoxins (750 ppb). The gross and microscopic lesions were confined to the liver. The biochemical analysis of the serum was consistent with the presence of liver damage. The presence of aflatoxins in the feeds and tissues of the dead sheep supports that the condition was due to aflatoxin poisoning.

Authors
Suliman, HB; Mohamed, AF; Awadelsied, NA; Shommein, AM
MLA Citation
Suliman, HB, Mohamed, AF, Awadelsied, NA, and Shommein, AM. "Acute mycotoxicosis in sheep: field cases." Vet Hum Toxicol 29.3 (June 1987): 241-243.
PMID
3604045
Source
pubmed
Published In
Veterinary and human toxicology
Volume
29
Issue
3
Publish Date
1987
Start Page
241
End Page
243

Normal serum activities of some diagnostic enzymes in dromedary camel in Sudan.

76 adult camel (30 males and 46 females) sera were surveyed for the normal activities of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine phospho-kinase (CPK), gamma-glutamyl transpeptidase (GGT) and lactate dehydrogenase (LDH). The values recorded for the above enzymes were compared to other data in the literature.

Authors
Eldirdiri, NI; Suliman, HB; Shommein, AM
MLA Citation
Eldirdiri, NI, Suliman, HB, and Shommein, AM. "Normal serum activities of some diagnostic enzymes in dromedary camel in Sudan." Vet Res Commun 11.3 (1987): 201-203.
PMID
2888228
Source
pubmed
Published In
Veterinary Research Communications
Volume
11
Issue
3
Publish Date
1987
Start Page
201
End Page
203

The pathological and biochemical effects of feeding fermented leaves of Cassia obtusifolia 'Kawal' to broiler chicks.

Fermented leaves of Cassia obtusifolia 'Kawal' were mixed in the food of broiler chicks at concentrations of 25, 50 and 100 g/Kg and then fed to chicks from 1 day to 8 weeks of age. Growth rate was depressed in relation to the concentration of Kawal. Lesions of an inflammatory-degenerative type were seen in the proventriculus, intestine, liver, heart, lungs and kidneys, their severity increasing with the amount of Kawal eaten. These were accompanied by similar increases in the activities of lactate dehydrogenase, alkaline phosphatase, glutamate oxaloacetate and glutamate pyruvate transaminases and in the concentrations of bilirubin, potassium, phosphorus, total lipids and carotenes in the blood and dose-related decreases in total protein, albumin, cholesterol, globulin, sodium, calcium and alkaline phosphatase in the blood. Birds fed on Kawal tended to become anaemic but white blood cell counts increased. It is concluded that Kawal even at an inclusion rate of 25 g/Kg is unacceptable as a protein supplement.

Authors
Suliman, HB; Shommein, AM; Shaddad, SA
MLA Citation
Suliman, HB, Shommein, AM, and Shaddad, SA. "The pathological and biochemical effects of feeding fermented leaves of Cassia obtusifolia 'Kawal' to broiler chicks." Avian Pathol 16.1 (1987): 43-49.
PMID
18766590
Source
pubmed
Published In
Avian Pathology
Volume
16
Issue
1
Publish Date
1987
Start Page
43
End Page
49
DOI
10.1080/03079458708436351

Toxic effect of the roasted and unroasted beans of Cassia occidentalis in goats.

The toxic effects of roasted and unroasted beans of the wild coffee, C occidentalis were compared. Both types of beans intoxicated goats in varying degrees, but roasting partially reduced the toxic effects of the beans. Histopathological, biochemical and enzyme histochemical studies showed that the toxin of C occidentalis damages the liver, vascular system, heart, and lungs.

Authors
Suliman, HB; Shommein, AM
MLA Citation
Suliman, HB, and Shommein, AM. "Toxic effect of the roasted and unroasted beans of Cassia occidentalis in goats." Vet Hum Toxicol 28.1 (February 1986): 6-11.
PMID
3010543
Source
pubmed
Published In
Veterinary and human toxicology
Volume
28
Issue
1
Publish Date
1986
Start Page
6
End Page
11

Some effects of imidocarb in goats.

Clinically normal Nubian goats were given the antiprotozoal drug imidocarb at single intramuscular doses of 6, 12, 18 and 24 mg/kg, and the various clinical, biochemical and pathological manifestations were recorded. At a dose of 6 mg/kg the drug produced no change in any of the parameters studied. At higher doses, the drug produced dose dependent changes which included increased heart and respiratory rates, increased defaecation, urination, depression, incoordination of movement, weakness of the hindlegs, recumbency, and finally death. Just prior to death, there was a significant decrease in the number of erythrocytes, and in packed cell volume, and haemoglobin concentration. In plasma there was an increase in the activity of aspartate transaminase, urea and creatinine concentrations and inhibition of cholinesterase activity. The main histopathological changes were associated with hepatic and renal damage. Three goats were pre-treated with atropine sulphate (1 mg/animal) and after one hour given imidocarb intramuscularly at a dose of 12 mg/kg. The changes were similar but much less severe when compared with those in animals given imidocarb alone at the same dose.

Authors
Ali, BH; Hassan, T; Suliman, HB; Abdelsalam, EB
MLA Citation
Ali, BH, Hassan, T, Suliman, HB, and Abdelsalam, EB. "Some effects of imidocarb in goats." Vet Hum Toxicol 27.6 (December 1985): 477-480.
PMID
4082455
Source
pubmed
Published In
Veterinary and human toxicology
Volume
27
Issue
6
Publish Date
1985
Start Page
477
End Page
480

The effects of Indigofera hochstetteri on goats.

Authors
Suliman, HB; Wasfi, IA; Tartour, G; Adam, SE
MLA Citation
Suliman, HB, Wasfi, IA, Tartour, G, and Adam, SE. "The effects of Indigofera hochstetteri on goats." Rev Elev Med Vet Pays Trop 36.4 (1983): 393-402.
PMID
6675077
Source
pubmed
Published In
Revue d'Elevage et de Medecine Veterinaire des Pays Tropicaux
Volume
36
Issue
4
Publish Date
1983
Start Page
393
End Page
402

The toxicity of Cassia occidentalis to goats.

The toxic effects of oral administration of Cassia occidentalis to goats was evaluated. The prominent signs of Cassia poisoning were diarrhea, inappetence, dyspnea, staggering, ataxia and recumbency. Lesions consisted of hemorrhages and congestion in the heart, lungs, abomasum and spleen, catarrhal enteritis, hepatic fatty change and necrosis, splenic hemosiderosis, pulmonary emphysema, necrosis and/or degeneration of the epithelial cells of the renal convoluted tubule, and packing of the glomeruli with endothelial and small round cells. These changes were accompanied by increases in GOT activity and in the serum concentrations of ammonia and urea, as well as by decreases in the total protein and calcium in serum. There were decreases in Hb, PCV and RCB, and increased leucocyte counts. Total lipids were higher in the liver, kidneys and heart of the Cassia-poisoned goats.

Authors
Suliman, HB; Wasfi, IA; Adam, SE
MLA Citation
Suliman, HB, Wasfi, IA, and Adam, SE. "The toxicity of Cassia occidentalis to goats." Vet Hum Toxicol 24.5 (October 1982): 326-330.
PMID
7135798
Source
pubmed
Published In
Veterinary and human toxicology
Volume
24
Issue
5
Publish Date
1982
Start Page
326
End Page
330

The toxic effects of Tephrosia apollinea on goats.

Authors
Suliman, HB; Wasfi, IA; Adam, SE
MLA Citation
Suliman, HB, Wasfi, IA, and Adam, SE. "The toxic effects of Tephrosia apollinea on goats." J Comp Pathol 92.2 (April 1982): 309-315.
PMID
7085947
Source
pubmed
Published In
Journal of Comparative Pathology
Volume
92
Issue
2
Publish Date
1982
Start Page
309
End Page
315
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