Ines Batinic-Haberle - Academia.edu (original) (raw)
Papers by Ines Batinic-Haberle
Free Radical Research, Oct 10, 2014
Herein we have demonstrated that both superoxide dismutase (SOD) mimic, cationic Mn(III) meso-tet... more Herein we have demonstrated that both superoxide dismutase (SOD) mimic, cationic Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl) porphyrin (MnTnHex-2-PyP 5+), and non-SOD mimic, anionic Mn(III) meso-tetrakis(4-carboxylatophenyl)porphyrin (MnTBAP 3−), protect against oxidative stress caused by spinal cord ischemia/reperfusion via suppression of nuclear factor kappa B (NF-κB) pro-inflammatory pathways. Earlier reports showed that Mn(III) Nalkylpyridylporphyrins were able to prevent the DNA binding of NF-κB in an aqueous system, whereas MnTBAP 3− was not. Here, for the first time, in a complex in vivo system-animal model of spinal cord injury-a similar impact of MnTBAP 3− , at a dose identical to that of MnTnHex-2-PyP 5+ , was demonstrated in NF-κB downregulation. Rats were treated subcutaneously at 1.5 mg/kg starting at 30 min before ischemia/reperfusion, and then every 12 h afterward for either 48 h or 7 days. The anti-inflammatory effects of both Mn porphyrins (MnPs) were demonstrated in the spinal cord tissue at both 48 h and 7 days. The down-regulation of NF-κ B, a major proinflammatory signaling protein regulating astrocyte activation, was detected and found to correlate well with the suppression of astrogliosis (as glial fibrillary acidic protein) by both MnPs. The markers of oxidative stress, lipid peroxidation and protein carbonyl formation, were significantly reduced by MnPs. The favorable impact of both MnPs on motor neurons (Tarlov score and inclined plane test) was assessed. No major changes in glutathione peroxidase-and SOD-like
Antioxidants & Redox Signaling, Sep 20, 2017
International Journal of Radiation Oncology Biology Physics, Sep 1, 2019
higher than that reported for historical controls. The impact of this treatment strategy on quali... more higher than that reported for historical controls. The impact of this treatment strategy on quality of life (QOL) is not well known. We sought to evaluate the QOL measures among adult LGG patients treated with RT+TMZ. Materials/Methods: The EuroQol 5 Dimensions questionnaire (EQ-5D) and Patient Health Questionnaire 9 (PHQ-9) were prospectively collected from a cohort of adult LGG (grade II) patients diagnosed between 1988 and 2018 who received RT+TMZ at a tertiary care institution. Questionnaires were obtained before outpatient visits every 2 to 3 months. EQ-5D assesses 5 dimensions of health including mobility, selfcare, completion of usual activities, pain/discomfort, and anxiety/ depression. An EQ-5D index is calculated from these 5 dimensions and ranges from 0 (death) to 1 (perfect health). PHQ-9 assesses depression based on 9 DSM-V criteria for major unipolar depression, providing a range from 0 to 27 in order of increasing severity. Differences in QOL outcomes against baseline (30-day window post-op), at 3, 6, 9, and 12 months, (AE 30 days) were analyzed by the Wilcoxon signedrank test. Results: Of the 103 pts included, the median age was 46 years (range: 19-77), and 55 (53%) were male. By molecular classification, cohort comprised of IDHmut-1p19q-codel, IDHmut-1p19q-noncodel, IDHmut-NOS, IDH1-R132H-negative, and unknown, in 14 (14%), 2 (2%), 20 (20%), 47 (46%), and 20 (20%) pts, respectively. Gross total resection was obtained for 17 (16%), near total resection for 9 (9%), subtotal resection for 15 (15%), and biopsy for 62 (60%) pts. By RTOG 9802 criteria, 63 (61%) were high risk, 13 (13%) were low risk, and 27 (27%) were unknown. The median radiation dose was 54 Gy (IQR: 54-59 Gy). Concurrent and adjuvant TMZ was delivered per Stupp protocol. Median follow-up was 2.1 years (range: 0.03-14.4) and median OS was 7.3 years (95% CI 3.7-13.7). The median (IQR) baseline PHQ-9 score was 4 (2-7) and did not change significantly over time. The median (IQR) PHQ-9 score was 2 (0-7) after 3 months (n Z 15, p Z 0.96), 5 (1-6) at 6 months (n Z 11, p > 0.99), 6 (2-9) at 9 months (nZ 8, p Z 0.30), and 3 (1-4) at 12 months (n Z 6, p Z 0.75). The median (IQR) baseline EQ-5D index score was 0.84 (0.83-1). The EQ-5D index score did not change significantly after 3 months 0.85 (0.80-0.86) (nZ9, pZ 0.74) and 6 months 0.71 (0.52-0.83) (nZ7, p Z 0.88). The sample sizes were insufficient for EQ-5D at 9 and 12 months. Conclusion: Adult LGG patients did not show significant changes in QOL measures (PHQ-9 and/or EQ-5D index) at 3 and 6 month post RT+TMZ compared to post-operative baseline. A larger sample size and longer follow-up is necessary to identify the impact on QOL of this treatment approach.
Breast Cancer Research, 2001
PloS one, 2018
We investigated the cytogenetic and gene expression responses of peripheral blood cells of non-hu... more We investigated the cytogenetic and gene expression responses of peripheral blood cells of non-human primates (NHP, Macaca mulatta) that were whole-thorax irradiated with a single dose of 10 Gy. In this model, partial irradiation of NHPs in the thoracic region (Whole Thorax Lung Irradiation, WTLI) allows the study of late radiation-induced lung injury, while avoiding acute radiation syndromes related to hematopoietic and gastrointestinal injury. A transient drop in circulating lymphocytes and platelets was seen by 9 days, followed by elevations in respiratory rate, circulating neutrophils, lymphocytes, and monocytes at 60-100 days, corresponding to computed tomography (CT) and histologic evidence of pneumonitis, and elective euthanasia of four animals. To evaluate long-term DNA damage in NHP peripheral blood lymphocytes after 10 Gy WTLI, we used the cytokinesis-block micronucleus (CBMN) assay to measure chromosomal aberrations as post-mitotic micronuclei in blood samples collected u...
Antioxidants & redox signaling, Jan 7, 2017
The susceptibility of CA1 over CA3 to damage from cerebral ischemia may be related to the differe... more The susceptibility of CA1 over CA3 to damage from cerebral ischemia may be related to the differences in reactive oxygen species (ROS) production/removal between the two hippocampal subfields. We aimed to measure CA1/CA3 differences in net ROS production in real time in the first 30 min of reperfusion in pyramidal cells. We aimed to determine the underlying cause of the differential vulnerability of CA1 and CA3. Real-time determinations of mitochondrial H2O2 and, independently, glutathione (GSH) redox status from roGFP-based probes in individual pyramidal cells in organotypic hippocampal cultures during oxygen-glucose deprivation (OGD)-reperfusion (RP) demonstrate a significantly more oxidizing environment during RP in CA1 than CA3 mitochondria. Protein levels (immunohistochemistry and Western blots), roGFP2-based probe measurements during controlled mitochondrial production of ROS, and thioredoxin reductase (TrxR) inhibition by auranofin are consistent with a more effective mitocho...
![Research paper thumbnail of Corrigendum to ‘An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins – From superoxide dismutation to H2O2-driven pathways’ [Redox Biology 5C (2015) 43–65]](https://attachments.academia-assets.com/117682719/thumbnails/1.jpg)
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Oncogene, 2011
Manganese superoxide dismutase is a nuclear encoded primary antioxidant enzyme localized exclusiv... more Manganese superoxide dismutase is a nuclear encoded primary antioxidant enzyme localized exclusively in the mitochondrial matrix. Genotoxic agents, such as ultraviolet (UV) radiation, generates oxidative stress and cause mitochondrial DNA (mtDNA) damage. The mtDNA polymerase (Polc), a major constituent of nucleoids, is responsible for the replication and repair of the mitochondrial genome. Recent studies suggest that the mitochondria contain fidelity proteins and MnSOD constitutes an integral part of the nucleoid complex. However, it is not known whether or how MnSOD participates in the mitochondrial repair processes. Using skin tissue from C57BL/6 mice exposed to UVB radiation, we demonstrate that MnSOD has a critical role in preventing mtDNA damage by protecting the function of Polc. Quantitative-PCR analysis shows an increase in mtDNA damage after UVB exposure. Immunofluorescence and immunoblotting studies demonstrate p53 translocation to the mitochondria and interaction with Polc after UVB exposure. The mtDNA immunoprecipitation assay with Polc and p53 antibodies in p53 þ / þ and p53 À/À mice demonstrates an interaction between MnSOD, p53 and Polc. The results suggest that these proteins form a complex for the repair of UVB-associated mtDNA damage. The data also demonstrate that UVB exposure injures the mtDNA D-loop in a p53-dependent manner. Using MnSOD-deficient mice we demonstrate that UVB-induced mtDNA damage is MnSOD dependent. Exposure to UVB results in nitration and inactivation of Polc, which is prevented by addition of the MnSOD mimetic Mn III TE-2-PyP 5 þ. These results demonstrate for the first time that MnSOD is a fidelity protein that maintains the activity of Polc by preventing UVB-induced nitration and inactivation of Polc. The data also demonstrate that MnSOD has a role along with p53 to prevent mtDNA damage.
Radiotherapy and Oncology, 2013
Pure and Applied Chemistry, 1996
Proceedings of the National Academy of Sciences, 2001
Plasma xanthine oxidase (XO) activity was defined as a source of enhanced vascular superoxide (O ... more Plasma xanthine oxidase (XO) activity was defined as a source of enhanced vascular superoxide (O \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{_{2}^{{\cdot}-}}}\end{equation*}\end{document} ) and hydrogen peroxide (H 2 O 2 ) production in both sickle cell disease (SCD) patients and knockout-transgenic SCD mice. There was a significant increase in the plasma XO activity of SCD patients that was similarly reflected in the SCD mouse model. Western blot and enzymatic analysis of liver tissue from SCD mice revealed decreased XO content. Hematoxylin and eosin staining of liver tissue of knockout-transgenic SCD mice indicated extensive hepatocellular injury that was accompanied by increased plasma content of the liver enzyme alanine aminotransferase. Immunocytochemical and enzymatic analysis of XO in thor...
Molecular cancer therapeutics, 2012
We recently identified superoxide dismutase (SOD) overexpression and decreased induction of react... more We recently identified superoxide dismutase (SOD) overexpression and decreased induction of reactive oxygen species (ROS)-mediated apoptosis in models of inflammatory breast cancer (IBC) cells with acquired therapeutic resistance. This population of cells has high expression of X-linked inhibitor of apoptosis protein (XIAP), which inhibits both extrinsic and intrinsic apoptosis pathways. We therefore wanted to evaluate the effect of classical apoptosis inducing agent TRAIL, a proapoptotic receptor agonist that selectively triggers death receptor (DR)-mediated apoptosis in cancer cells, in the IBC acquired resistance model. XIAP levels and subsequent inhibition of caspase activity inversely correlated with TRAIL sensitivity our models of IBC. These include SUM149, a basal-type cell line isolated from primary IBC tumors, and isogenic SUM149-derived lines rSUM149 and SUM149 wtXIAP, models of acquired therapeutic resistance with endogenous and exogenous XIAP overexpression respectively....
Journal of Biological Chemistry, 1998
Free Radical Research, Oct 10, 2014
Herein we have demonstrated that both superoxide dismutase (SOD) mimic, cationic Mn(III) meso-tet... more Herein we have demonstrated that both superoxide dismutase (SOD) mimic, cationic Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl) porphyrin (MnTnHex-2-PyP 5+), and non-SOD mimic, anionic Mn(III) meso-tetrakis(4-carboxylatophenyl)porphyrin (MnTBAP 3−), protect against oxidative stress caused by spinal cord ischemia/reperfusion via suppression of nuclear factor kappa B (NF-κB) pro-inflammatory pathways. Earlier reports showed that Mn(III) Nalkylpyridylporphyrins were able to prevent the DNA binding of NF-κB in an aqueous system, whereas MnTBAP 3− was not. Here, for the first time, in a complex in vivo system-animal model of spinal cord injury-a similar impact of MnTBAP 3− , at a dose identical to that of MnTnHex-2-PyP 5+ , was demonstrated in NF-κB downregulation. Rats were treated subcutaneously at 1.5 mg/kg starting at 30 min before ischemia/reperfusion, and then every 12 h afterward for either 48 h or 7 days. The anti-inflammatory effects of both Mn porphyrins (MnPs) were demonstrated in the spinal cord tissue at both 48 h and 7 days. The down-regulation of NF-κ B, a major proinflammatory signaling protein regulating astrocyte activation, was detected and found to correlate well with the suppression of astrogliosis (as glial fibrillary acidic protein) by both MnPs. The markers of oxidative stress, lipid peroxidation and protein carbonyl formation, were significantly reduced by MnPs. The favorable impact of both MnPs on motor neurons (Tarlov score and inclined plane test) was assessed. No major changes in glutathione peroxidase-and SOD-like
Antioxidants & Redox Signaling, Sep 20, 2017
International Journal of Radiation Oncology Biology Physics, Sep 1, 2019
higher than that reported for historical controls. The impact of this treatment strategy on quali... more higher than that reported for historical controls. The impact of this treatment strategy on quality of life (QOL) is not well known. We sought to evaluate the QOL measures among adult LGG patients treated with RT+TMZ. Materials/Methods: The EuroQol 5 Dimensions questionnaire (EQ-5D) and Patient Health Questionnaire 9 (PHQ-9) were prospectively collected from a cohort of adult LGG (grade II) patients diagnosed between 1988 and 2018 who received RT+TMZ at a tertiary care institution. Questionnaires were obtained before outpatient visits every 2 to 3 months. EQ-5D assesses 5 dimensions of health including mobility, selfcare, completion of usual activities, pain/discomfort, and anxiety/ depression. An EQ-5D index is calculated from these 5 dimensions and ranges from 0 (death) to 1 (perfect health). PHQ-9 assesses depression based on 9 DSM-V criteria for major unipolar depression, providing a range from 0 to 27 in order of increasing severity. Differences in QOL outcomes against baseline (30-day window post-op), at 3, 6, 9, and 12 months, (AE 30 days) were analyzed by the Wilcoxon signedrank test. Results: Of the 103 pts included, the median age was 46 years (range: 19-77), and 55 (53%) were male. By molecular classification, cohort comprised of IDHmut-1p19q-codel, IDHmut-1p19q-noncodel, IDHmut-NOS, IDH1-R132H-negative, and unknown, in 14 (14%), 2 (2%), 20 (20%), 47 (46%), and 20 (20%) pts, respectively. Gross total resection was obtained for 17 (16%), near total resection for 9 (9%), subtotal resection for 15 (15%), and biopsy for 62 (60%) pts. By RTOG 9802 criteria, 63 (61%) were high risk, 13 (13%) were low risk, and 27 (27%) were unknown. The median radiation dose was 54 Gy (IQR: 54-59 Gy). Concurrent and adjuvant TMZ was delivered per Stupp protocol. Median follow-up was 2.1 years (range: 0.03-14.4) and median OS was 7.3 years (95% CI 3.7-13.7). The median (IQR) baseline PHQ-9 score was 4 (2-7) and did not change significantly over time. The median (IQR) PHQ-9 score was 2 (0-7) after 3 months (n Z 15, p Z 0.96), 5 (1-6) at 6 months (n Z 11, p > 0.99), 6 (2-9) at 9 months (nZ 8, p Z 0.30), and 3 (1-4) at 12 months (n Z 6, p Z 0.75). The median (IQR) baseline EQ-5D index score was 0.84 (0.83-1). The EQ-5D index score did not change significantly after 3 months 0.85 (0.80-0.86) (nZ9, pZ 0.74) and 6 months 0.71 (0.52-0.83) (nZ7, p Z 0.88). The sample sizes were insufficient for EQ-5D at 9 and 12 months. Conclusion: Adult LGG patients did not show significant changes in QOL measures (PHQ-9 and/or EQ-5D index) at 3 and 6 month post RT+TMZ compared to post-operative baseline. A larger sample size and longer follow-up is necessary to identify the impact on QOL of this treatment approach.
Breast Cancer Research, 2001
PloS one, 2018
We investigated the cytogenetic and gene expression responses of peripheral blood cells of non-hu... more We investigated the cytogenetic and gene expression responses of peripheral blood cells of non-human primates (NHP, Macaca mulatta) that were whole-thorax irradiated with a single dose of 10 Gy. In this model, partial irradiation of NHPs in the thoracic region (Whole Thorax Lung Irradiation, WTLI) allows the study of late radiation-induced lung injury, while avoiding acute radiation syndromes related to hematopoietic and gastrointestinal injury. A transient drop in circulating lymphocytes and platelets was seen by 9 days, followed by elevations in respiratory rate, circulating neutrophils, lymphocytes, and monocytes at 60-100 days, corresponding to computed tomography (CT) and histologic evidence of pneumonitis, and elective euthanasia of four animals. To evaluate long-term DNA damage in NHP peripheral blood lymphocytes after 10 Gy WTLI, we used the cytokinesis-block micronucleus (CBMN) assay to measure chromosomal aberrations as post-mitotic micronuclei in blood samples collected u...
Antioxidants & redox signaling, Jan 7, 2017
The susceptibility of CA1 over CA3 to damage from cerebral ischemia may be related to the differe... more The susceptibility of CA1 over CA3 to damage from cerebral ischemia may be related to the differences in reactive oxygen species (ROS) production/removal between the two hippocampal subfields. We aimed to measure CA1/CA3 differences in net ROS production in real time in the first 30 min of reperfusion in pyramidal cells. We aimed to determine the underlying cause of the differential vulnerability of CA1 and CA3. Real-time determinations of mitochondrial H2O2 and, independently, glutathione (GSH) redox status from roGFP-based probes in individual pyramidal cells in organotypic hippocampal cultures during oxygen-glucose deprivation (OGD)-reperfusion (RP) demonstrate a significantly more oxidizing environment during RP in CA1 than CA3 mitochondria. Protein levels (immunohistochemistry and Western blots), roGFP2-based probe measurements during controlled mitochondrial production of ROS, and thioredoxin reductase (TrxR) inhibition by auranofin are consistent with a more effective mitocho...
Oncogene, 2011
Manganese superoxide dismutase is a nuclear encoded primary antioxidant enzyme localized exclusiv... more Manganese superoxide dismutase is a nuclear encoded primary antioxidant enzyme localized exclusively in the mitochondrial matrix. Genotoxic agents, such as ultraviolet (UV) radiation, generates oxidative stress and cause mitochondrial DNA (mtDNA) damage. The mtDNA polymerase (Polc), a major constituent of nucleoids, is responsible for the replication and repair of the mitochondrial genome. Recent studies suggest that the mitochondria contain fidelity proteins and MnSOD constitutes an integral part of the nucleoid complex. However, it is not known whether or how MnSOD participates in the mitochondrial repair processes. Using skin tissue from C57BL/6 mice exposed to UVB radiation, we demonstrate that MnSOD has a critical role in preventing mtDNA damage by protecting the function of Polc. Quantitative-PCR analysis shows an increase in mtDNA damage after UVB exposure. Immunofluorescence and immunoblotting studies demonstrate p53 translocation to the mitochondria and interaction with Polc after UVB exposure. The mtDNA immunoprecipitation assay with Polc and p53 antibodies in p53 þ / þ and p53 À/À mice demonstrates an interaction between MnSOD, p53 and Polc. The results suggest that these proteins form a complex for the repair of UVB-associated mtDNA damage. The data also demonstrate that UVB exposure injures the mtDNA D-loop in a p53-dependent manner. Using MnSOD-deficient mice we demonstrate that UVB-induced mtDNA damage is MnSOD dependent. Exposure to UVB results in nitration and inactivation of Polc, which is prevented by addition of the MnSOD mimetic Mn III TE-2-PyP 5 þ. These results demonstrate for the first time that MnSOD is a fidelity protein that maintains the activity of Polc by preventing UVB-induced nitration and inactivation of Polc. The data also demonstrate that MnSOD has a role along with p53 to prevent mtDNA damage.
Radiotherapy and Oncology, 2013
Pure and Applied Chemistry, 1996
Proceedings of the National Academy of Sciences, 2001
Plasma xanthine oxidase (XO) activity was defined as a source of enhanced vascular superoxide (O ... more Plasma xanthine oxidase (XO) activity was defined as a source of enhanced vascular superoxide (O \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{_{2}^{{\cdot}-}}}\end{equation*}\end{document} ) and hydrogen peroxide (H 2 O 2 ) production in both sickle cell disease (SCD) patients and knockout-transgenic SCD mice. There was a significant increase in the plasma XO activity of SCD patients that was similarly reflected in the SCD mouse model. Western blot and enzymatic analysis of liver tissue from SCD mice revealed decreased XO content. Hematoxylin and eosin staining of liver tissue of knockout-transgenic SCD mice indicated extensive hepatocellular injury that was accompanied by increased plasma content of the liver enzyme alanine aminotransferase. Immunocytochemical and enzymatic analysis of XO in thor...
Molecular cancer therapeutics, 2012
We recently identified superoxide dismutase (SOD) overexpression and decreased induction of react... more We recently identified superoxide dismutase (SOD) overexpression and decreased induction of reactive oxygen species (ROS)-mediated apoptosis in models of inflammatory breast cancer (IBC) cells with acquired therapeutic resistance. This population of cells has high expression of X-linked inhibitor of apoptosis protein (XIAP), which inhibits both extrinsic and intrinsic apoptosis pathways. We therefore wanted to evaluate the effect of classical apoptosis inducing agent TRAIL, a proapoptotic receptor agonist that selectively triggers death receptor (DR)-mediated apoptosis in cancer cells, in the IBC acquired resistance model. XIAP levels and subsequent inhibition of caspase activity inversely correlated with TRAIL sensitivity our models of IBC. These include SUM149, a basal-type cell line isolated from primary IBC tumors, and isogenic SUM149-derived lines rSUM149 and SUM149 wtXIAP, models of acquired therapeutic resistance with endogenous and exogenous XIAP overexpression respectively....
Journal of Biological Chemistry, 1998