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  1. Article: Peroxynitrite induced mitochondrial biogenesis following MnSOD knockdown in normal rat kidney (NRK) cells.

    Marine, Akira / Krager, Kimberly J / Aykin-Burns, Nukhet / Macmillan-Crow, Lee Ann

    Redox biology

    2014  Volume 2, Page(s) 348–357

    Abstract: Superoxide is widely regarded as the primary reactive oxygen species (ROS) which initiates downstream oxidative stress. Increased oxidative stress contributes, in part, to many disease conditions such as cancer, atherosclerosis, ischemia/reperfusion, ... ...

    Abstract Superoxide is widely regarded as the primary reactive oxygen species (ROS) which initiates downstream oxidative stress. Increased oxidative stress contributes, in part, to many disease conditions such as cancer, atherosclerosis, ischemia/reperfusion, diabetes, aging, and neurodegeneration. Manganese superoxide dismutase (MnSOD) catalyzes the dismutation of superoxide into hydrogen peroxide which can then be further detoxified by other antioxidant enzymes. MnSOD is critical in maintaining the normal function of mitochondria, thus its inactivation is thought to lead to compromised mitochondria. Previously, our laboratory observed increased mitochondrial biogenesis in a novel kidney-specific MnSOD knockout mouse. The current study used transient siRNA mediated MnSOD knockdown of normal rat kidney (NRK) cells as the in vitro model, and confirmed functional mitochondrial biogenesis evidenced by increased PGC1α expression, mitochondrial DNA copy numbers and integrity, electron transport chain protein CORE II, mitochondrial mass, oxygen consumption rate, and overall ATP production. Further mechanistic studies using mitoquinone (MitoQ), a mitochondria-targeted antioxidant and L-NAME, a nitric oxide synthase (NOS) inhibitor demonstrated that peroxynitrite (at low micromolar levels) induced mitochondrial biogenesis. These findings provide the first evidence that low levels of peroxynitrite can initiate a protective signaling cascade involving mitochondrial biogenesis which may help to restore mitochondrial function following transient MnSOD inactivation.
    MeSH term(s) Animals ; Cell Line ; DNA, Mitochondrial/metabolism ; Electron Transport Chain Complex Proteins/metabolism ; Gene Knockdown Techniques ; Kidney/cytology ; Kidney/metabolism ; Mitochondria/physiology ; Models, Biological ; NG-Nitroarginine Methyl Ester/pharmacology ; Organophosphorus Compounds/pharmacology ; Peroxynitrous Acid/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase/metabolism ; Ubiquinone/analogs & derivatives ; Ubiquinone/pharmacology
    Chemical Substances DNA, Mitochondrial ; Electron Transport Chain Complex Proteins ; Organophosphorus Compounds ; Reactive Oxygen Species ; Ubiquinone (1339-63-5) ; Peroxynitrous Acid (14691-52-2) ; mitoquinone (47BYS17IY0) ; Superoxide Dismutase (EC 1.15.1.1) ; superoxide dismutase 2 (EC 1.15.1.1) ; NG-Nitroarginine Methyl Ester (V55S2QJN2X)
    Language English
    Publishing date 2014-01-23
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2701011-9
    ISSN 2213-2317
    ISSN 2213-2317
    DOI 10.1016/j.redox.2014.01.014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Cold preservation mediated renal injury: involvement of mitochondrial oxidative stress.

    Saba, Hamida / Munusamy, Shankar / Macmillan-Crow, Lee Ann

    Renal failure

    2008  Volume 30, Issue 2, Page(s) 125–133

    Abstract: Cold preservation has greatly facilitated the use of cadaveric kidneys for renal transplantation, but, clearly, damage occurs during both the preservation episode and the reperfusion phase (following transplantation). The aims of this study were twofold: ...

    Abstract Cold preservation has greatly facilitated the use of cadaveric kidneys for renal transplantation, but, clearly, damage occurs during both the preservation episode and the reperfusion phase (following transplantation). The aims of this study were twofold: to develop an in vivo model that was capable of evaluating renal function at early time points following cold preservation, and to evaluate the extent of renal mitochondrial damage that occurs following short periods of cold preservation in vivo. To accomplish these goals, we developed a novel rat model of in vivo renal cold ischemia followed by warm reperfusion (cold I/R) which avoided the complexity involved with transplantation. Briefly, after a right nephrectomy, cold I/R was initiated via pulsatile perfusion (40 minutes) of the left kidney with a cold University of Wisconsin solution followed by 18 hours of warm reperfusion. Cold I/R resulted in significant renal injury, nitrotyrosine production, and inactivation of the key mitochondrial antioxidant enzyme, manganese superoxide dismutase. Furthermore, the activities of the mitochondrial respiratory complexes were significantly reduced following cold I/R. In conclusion, short-term cold I/R results in inactivation of MnSOD, which may lead to the inhibition of mitochondrial complexes and subsequent renal injury. These data suggest that compounds designed to prevent early mitochondrial injury in kidneys that undergo cold preservation would significantly improve renal function and graft survival following transplantation.
    MeSH term(s) Analysis of Variance ; Animals ; Blotting, Western ; Cryopreservation/methods ; Disease Models, Animal ; Graft Rejection ; Graft Survival ; Immunohistochemistry ; Ischemic Preconditioning/adverse effects ; Ischemic Preconditioning/methods ; Kidney ; Kidney Function Tests ; Kidney Transplantation/adverse effects ; Kidney Transplantation/methods ; Male ; Mitochondria/pathology ; Organ Preservation/adverse effects ; Organ Preservation/methods ; Oxidative Stress ; Probability ; Random Allocation ; Rats ; Rats, Inbred F344 ; Reperfusion Injury/etiology ; Reperfusion Injury/physiopathology ; Risk Factors ; Sensitivity and Specificity ; Superoxide Dismutase/metabolism
    Chemical Substances Superoxide Dismutase (EC 1.15.1.1)
    Language English
    Publishing date 2008
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 632949-4
    ISSN 1525-6049 ; 0886-022X
    ISSN (online) 1525-6049
    ISSN 0886-022X
    DOI 10.1080/08860220701813327
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1331: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: MitoQ blunts mitochondrial and renal damage during cold preservation of porcine kidneys.

    Parajuli, Nirmala / Campbell, Lia H / Marine, Akira / Brockbank, Kelvin G M / Macmillan-Crow, Lee Ann

    PloS one

    2012  Volume 7, Issue 11, Page(s) e48590

    Abstract: Cold preservation has greatly facilitated the use of cadaveric kidneys for transplantation but damage occurs during the preservation episode. It is well established that oxidant production increases during cold renal preservation and mitochondria are a ... ...

    Abstract Cold preservation has greatly facilitated the use of cadaveric kidneys for transplantation but damage occurs during the preservation episode. It is well established that oxidant production increases during cold renal preservation and mitochondria are a key target for injury. Our laboratory has demonstrated that cold storage of renal cells and rat kidneys leads to increased mitochondrial superoxide levels and mitochondrial electron transport chain damage, and that addition of Mitoquinone (MitoQ) to the preservation solutions blunted this injury. In order to better translate animal studies, the inclusion of large animal models is necessary to develop safe preclinical protocols. Therefore, we tested the hypothesis that addition of MitoQ to cold storage solution preserves mitochondrial function by decreasing oxidative stress, leading to less renal tubular damage during cold preservation of porcine kidneys employing a standard criteria donor model. Results showed that cold storage significantly induced oxidative stress (nitrotyrosine), renal tubular damage, and cell death. Using High Resolution Respirometry and fresh porcine kidney biopsies to assess mitochondrial function we showed that MitoQ significantly improved complex II/III respiration of the electron transport chain following 24 hours of cold storage. In addition, MitoQ blunted oxidative stress, renal tubular damage, and cell death after 48 hours. These results suggested that MitoQ decreased oxidative stress, tubular damage and cell death by improving mitochondrial function during cold storage. Therefore this compound should be considered as an integral part of organ preservation solution prior to transplantation.
    MeSH term(s) Animals ; Cell Death/drug effects ; Cryopreservation ; Electron Transport/drug effects ; In Situ Nick-End Labeling ; Kidney Tubules/drug effects ; Kidney Tubules/pathology ; Male ; Mitochondria/drug effects ; Mitochondria/pathology ; Nitrosation/drug effects ; Organ Preservation ; Organophosphorus Compounds/pharmacology ; Oxidative Stress/drug effects ; Proteins/metabolism ; Rats ; Sus scrofa ; Ubiquinone/analogs & derivatives ; Ubiquinone/pharmacology
    Chemical Substances Organophosphorus Compounds ; Proteins ; Ubiquinone (1339-63-5) ; mitoquinone (47BYS17IY0)
    Language English
    Publishing date 2012-11-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0048590
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Generation and characterization of a novel kidney-specific manganese superoxide dismutase knockout mouse.

    Parajuli, Nirmala / Marine, Akira / Simmons, Sloane / Saba, Hamida / Mitchell, Tanecia / Shimizu, Takahiko / Shirasawa, Takuji / Macmillan-Crow, Lee Ann

    Free radical biology & medicine

    2011  Volume 51, Issue 2, Page(s) 406–416

    Abstract: Inactivation of manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant, has been associated with renal disorders and often results in detrimental downstream events that are mechanistically not clear. Development of an animal model that ... ...

    Abstract Inactivation of manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant, has been associated with renal disorders and often results in detrimental downstream events that are mechanistically not clear. Development of an animal model that exhibits kidney-specific deficiency of MnSOD would be extremely beneficial in exploring the downstream events that occur following MnSOD inactivation. Using Cre-Lox recombination technology, kidney-specific MnSOD deficient mice (both 100% and 50%) were generated that exhibited low expression of MnSOD in discrete renal cell types and reduced enzymatic activity within the kidney. These kidney-specific 100% KO mice possessed a normal life-span, although it was interesting that the mice were smaller. Consistent with the important role in scavenging superoxide radicals, the kidney-specific KO mice showed a significant increase in oxidative stress (tyrosine nitration) in a gene-dose dependent manner. In addition, loss of MnSOD resulted in mild renal damage (tubular dilation and cell swelling). Hence, this novel mouse model will aid in determining the specific role (local and/or systemic) governed by MnSOD within certain kidney cells. Moreover, these mice will serve as a powerful tool to explore molecular mechanisms that occur downstream of MnSOD inactivation in renal disorders or possibly in other pathologies that rely on normal renal function.
    MeSH term(s) Animals ; Base Sequence ; Blood Glucose/analysis ; Creatinine/blood ; DNA Primers ; Female ; Immunohistochemistry ; Kidney/enzymology ; Mice ; Mice, Transgenic ; Superoxide Dismutase/antagonists & inhibitors ; Superoxide Dismutase/genetics ; Superoxide Dismutase/metabolism
    Chemical Substances Blood Glucose ; DNA Primers ; Creatinine (AYI8EX34EU) ; Superoxide Dismutase (EC 1.15.1.1)
    Language English
    Publishing date 2011-04-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 807032-5
    ISSN 1873-4596 ; 0891-5849
    ISSN (online) 1873-4596
    ISSN 0891-5849
    DOI 10.1016/j.freeradbiomed.2011.04.024
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2109: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Alteration of renal respiratory Complex-III during experimental type-1 diabetes.

    Munusamy, Shankar / Saba, Hamida / Mitchell, Tanecia / Megyesi, Judit K / Brock, Robert W / Macmillan-Crow, Lee Ann

    BMC endocrine disorders

    2009  Volume 9, Page(s) 2

    Abstract: Background: Diabetes has become the single most common cause for end-stage renal disease in the United States. It has been established that mitochondrial damage occurs during diabetes; however, little is known about what initiates mitochondrial injury ... ...

    Abstract Background: Diabetes has become the single most common cause for end-stage renal disease in the United States. It has been established that mitochondrial damage occurs during diabetes; however, little is known about what initiates mitochondrial injury and oxidant production during the early stages of diabetes. Inactivation of mitochondrial respiratory complexes or alteration of their critical subunits can lead to generation of mitochondrial oxidants, mitochondrial damage, and organ injury. Thus, one goal of this study was to determine the status of mitochondrial respiratory complexes in the rat kidney during the early stages of diabetes (5-weeks post streptozotocin injection).
    Methods: Mitochondrial complex activity assays, blue native gel electrophoresis (BN-PAGE), Complex III immunoprecipitation, and an ATP assay were performed to examine the effects of diabetes on the status of respiratory complexes and energy levels in renal mitochondria. Creatinine clearance and urine albumin excretion were measured to assess the status of renal function in our model.
    Results: Interestingly, of all four respiratory complexes only cytochrome c reductase (Complex-III) activity was significantly decreased, whereas two Complex III subunits, Core 2 protein and Rieske protein, were up regulated in the diabetic renal mitochondria. The BN-PAGE data suggested that Complex III failed to assemble correctly, which could also explain the compensatory upregulation of specific Complex III subunits. In addition, the renal F0F1-ATPase activity and ATP levels were increased during diabetes.
    Conclusion: In summary, these findings show for the first time that early (and selective) inactivation of Complex-III may contribute to the mitochondrial oxidant production which occurs in the early stages of diabetes.
    Language English
    Publishing date 2009-01-23
    Publishing country England
    Document type Journal Article
    ISSN 1472-6823
    ISSN (online) 1472-6823
    DOI 10.1186/1472-6823-9-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Delineating liver events in trichloroethylene-induced autoimmune hepatitis.

    Gilbert, Kathleen M / Przybyla, Beata / Pumford, Neil R / Han, Tao / Fuscoe, James / Schnackenberg, Laura K / Holland, Ricky D / Doss, Jason C / Macmillan-Crow, Lee Ann / Blossom, Sarah J

    Chemical research in toxicology

    2009  Volume 22, Issue 4, Page(s) 626–632

    Abstract: Exposure to the environmental pollutant trichloroethylene (TCE) has been linked to autoimmune disease development in humans. Chronic (32-week) low-level exposure to TCE has been shown to promote autoimmune hepatitis in association with CD4(+) T cell ... ...

    Abstract Exposure to the environmental pollutant trichloroethylene (TCE) has been linked to autoimmune disease development in humans. Chronic (32-week) low-level exposure to TCE has been shown to promote autoimmune hepatitis in association with CD4(+) T cell activation in autoimmune-prone MRL+/+ mice. MRL+/+ mice are usually thought of as a model of systemic lupus rather than an organ-specific disease such as autoimmune hepatitis. Consequently, the present study examined gene expression and metabolites to delineate the liver events that skewed the autoimmune response toward that organ in TCE-treated mice. Female MRL+/+ mice were treated with 0.5 mg/mL TCE in their drinking water. The results showed that TCE-induced autoimmune hepatitis could be detected in as little as 26 weeks. TCE exposure also generated a time-dependent increase in the number of antibodies specific for liver proteins. The gene expression correlated with the metabolite analysis to show that TCE upregulated the methionine/homocysteine pathway in the liver after 26 weeks of exposure. The results also showed that TCE exposure altered the expression of selective hepatic genes associated with immunity and inflammation. On the basis of these results, future mechanistic studies will focus on how alterations in genes associated with immunity and inflammation, in conjunction with protein alterations in the liver, promote liver immunogenicity in TCE-treated MRL+/+ mice.
    MeSH term(s) Administration, Oral ; Animals ; Autoimmune Diseases/chemically induced ; Autoimmune Diseases/immunology ; Autoimmune Diseases/metabolism ; CD4-Positive T-Lymphocytes/immunology ; Chemical and Drug Induced Liver Injury/immunology ; Chemical and Drug Induced Liver Injury/metabolism ; Chemical and Drug Induced Liver Injury/pathology ; Environmental Pollutants/administration & dosage ; Environmental Pollutants/toxicity ; Female ; Gene Expression Regulation ; Hepatitis, Autoimmune/immunology ; Hepatitis, Autoimmune/metabolism ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Mice ; Mice, Inbred MRL lpr ; Oligonucleotide Array Sequence Analysis ; Oxidative Stress/drug effects ; Principal Component Analysis ; Trichloroethylene/administration & dosage ; Trichloroethylene/toxicity
    Chemical Substances Environmental Pollutants ; Trichloroethylene (290YE8AR51)
    Language English
    Publishing date 2009-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639353-6
    ISSN 1520-5010 ; 0893-228X
    ISSN (online) 1520-5010
    ISSN 0893-228X
    DOI 10.1021/tx800409r
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2320: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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