Journal articles: 'MnSOD mimic'

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ROGERS, Richard J., Sarah E. CHESROWN, Shiuhyang KUO, Joan M. MONNIER, and Harry S. NICK. "Cytokine-inducible enhancer with promoter activity in both the rat and human manganese-superoxide dismutase genes." Biochemical Journal 347, no. 1 (March 27, 2000): 233–42. http://dx.doi.org/10.1042/bj3470233.

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Diverse pro-inflammatory mediators regulate transcription of the gene (MnSOD) encoding the mitochondrial anti-oxidant protein manganese-superoxide dismutase. Understanding the regulation of this gene is crucial to comprehending its role in cytoprotection. In transfected lung epithelial cells, a human-growth-hormone reporter gene system was utilized to identify a potential enhancer in the MnSOD genomic fragment previously shown to contain multiple DNase-I-hypersensitive sites. Northern analysis demonstrated a 10-20-fold increase in response to pro-inflammatory mediators. Inclusion of the MnSOD genomic fragment in reporter constructs was necessary to mimic these stimulus-dependent endogenous levels. The inducible enhancer element was localized to a 260 bp fragment in intron 2, coinciding with a previously defined DNase-I-hypersensitive site. This element functions in an orientation- and position-independent manner as well as with the heterologous thymidine kinase promoter. In addition, we have demonstrated that a homologous sequence within the human MnSOD gene exhibits identical enhancer activity. A novel characteristic of the rat and human enhancer elements involves the ability to promote cytokine-inducible transcription in the absence of a classical promoter.

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Yuan, Yanggang, Hui Wang, Yingyi Wu, Bo Zhang, Ningning Wang, Huijuan Mao, and Changying Xing. "P53 Contributes to Cisplatin Induced Renal Oxidative Damage via Regulating P66shc and MnSOD." Cellular Physiology and Biochemistry 37, no. 4 (2015): 1240–56. http://dx.doi.org/10.1159/000430247.

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Background/Aims: Cisplatin is widely used to treat malignancies. However, its major limitation is the development of dose-dependent nephrotoxicity. The precise mechanisms of cisplatin-induced kidney damage remain unclear. Previous study demonstrated the central role of mitochondrial ROS (mtROS) in the pathogenesis of cisplatin nephrotoxicity. The purpose of this study was to explore the mechanism of mtROS regulation in cisplatin nephrotoxicity. Methods: p53, MnSOD and p66shc were detected at mRNA and protein levels by qPCR and western blot in HK2 cells. mtROS levels were determined by DCFDA and MitoSOX staining. Cell viability and cell apoptosis were accessed by CCK-8 assay, TUNEL assay and flow cytometry, respectivesly. siRNAs were used to knock down p53 and p66shc expression and subsequent changes were observed. In vivo assays using a mouse model of cisplatin-induced acute kidney injury were used to validate the in vitro results. Results: In HK2 cells, cisplatin exposure decreased the MnSOD and increased the expression of p53 and p66shc. MnTBAP, a MnSOD mimic, blocked cisplatin-induced the generation of mtROS and cell injury. P66shc and p53 siRNAs rendered renal cells resistant to cisplatin-induced mtROS production and cell death. Furthermore, knockdown of p53 restored MnSOD and inhibiting p66shc. Consistent with these results, we revealed that p53 inhibitor reduced cisplatin-induced oxidative stress and apoptosis by regulating MnSOD and p66shc in the kidney of cisplatin-treated mice. Conclusion: Our study identifies activation of p53 signalling as a potential strategy for reducing the nephrotoxicity associated with cisplatin treatments and, as a result, broadens the therapeutic window of this chemotherapeutic agent.

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Dewhirst, M. W., K. Ashcraft, I. Batinic-Haberle, I. Spasojevic, and D. M. Brizel. "A Novel Mnsod Mimic Widens the Therapeutic Margin by Simultaneously Radioprotecting Normal Tissue and Radiosensitizing Tumor." International Journal of Radiation Oncology*Biology*Physics 88, no. 2 (February 2014): 468. http://dx.doi.org/10.1016/j.ijrobp.2013.11.028.

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Mathieu, Emilie, Anne-Sophie Bernard, Nicolas Delsuc, Elodie Quévrain, Géraldine Gazzah, Barry Lai, Florian Chain, et al. "A Cell-Penetrant Manganese Superoxide Dismutase (MnSOD) Mimic Is Able To Complement MnSOD and Exerts an Antiinflammatory Effect on Cellular and Animal Models of Inflammatory Bowel Diseases." Inorganic Chemistry 56, no. 5 (February 15, 2017): 2545–55. http://dx.doi.org/10.1021/acs.inorgchem.6b02695.

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Inclán, Mario, María Teresa Albelda, Salvador Blasco, Carolina Serena, Javier Ugarte Chicote, Antonio García-España, and Enrique García-España. "Mn(II) Complexes of Enlarged Scorpiand-Type Azamacrocycles as Mimetics of MnSOD Enzyme." Applied Sciences 12, no. 5 (February 26, 2022): 2447. http://dx.doi.org/10.3390/app12052447.

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Living organisms depend on superoxide dismutase (SOD) enzymes to shield themselves from the deleterious effects of superoxide radical. In humans, alterations of these protective mechanisms have been linked to the pathogenesis of many diseases. However, the therapeutic use of the native enzyme is hindered by, among other things, its high molecular size, low stability, and immunogenicity. For this reason, synthetic SOD mimetic compounds of low molecular weight may have therapeutic potential. We present here three low-molecular-weight compounds, whose Mn2+ complexes can mimic, at least partially, the protective activity of SOD-enzymes. These compounds were characterized by NMR, potentiometry, and, to test whether they have protective activity in vitro, by their capacity to restore the growth of SOD-deficient strains of E. coli. In this report, we provide evidence that these compounds form stable complexes with Mn2+ and have an in vitro protective effect, restoring up to 75% the growth of the SOD-deficient E. coli.

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Pedullà, Marcella, Riccardo d'Aquino, Vincenzo Desiderio, Francesco de Francesco, Andrew Puca, and Gianpaolo Papaccio. "MnSOD mimic compounds can counteract mechanical stress and islet β cell apoptosis, although at appropriate concentration ranges." Journal of Cellular Physiology 212, no. 2 (February 20, 2007): 432–38. http://dx.doi.org/10.1002/jcp.21034.

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González Arbeláez, Luisa F., Ignacio A. Pérez Núñez, and Susana M. Mosca. "Gsk-3βInhibitors Mimic the Cardioprotection Mediated by Ischemic Pre- and Postconditioning in Hypertensive Rats." BioMed Research International 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/317456.

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The aim of this study was to examine the effects of GSK-3βinhibitors compared with PRE and POS in spontaneously hypertensive rats (SHR). Isolated hearts were submitted to the following protocols: IC: 45 min global ischemia (GI) and 1-hour reperfusion (R); PRE: a cycle of 5 min GI and 10 minutes of R prior to 45 min GI; POS: three cycles of 30 sec GI/30 sec R at the start of R. Other hearts received lithium chloride (LiCl) or indirubin-3′-monoxime,5-iodo-(IMI) as GSK-3βinhibitors. All interventions reduced the infarct size observed in IC group. The expressions of P-GSK-3βand P-Akt decreased in IC and were restored after PRE, POS, and GSK-3βinhibitors treatments. An increase of cytosolic MnSOD activity and lipid peroxidation and a decrease of GSH content observed in IC hearts were attenuated in PRE, POS, and LiCl or IMI treatments. An increase of P-GSK-3β/VDAC physical association and a partial recovery of mitochondrial permeability were also detected after interventions. These data show that, in SHR hearts, GSK-3βinhibitors mimic the cardioprotection afforded by PRE and POS and suggest that a decrease in mitochondrial permeability mediated by P-GSK-3β/VDAC interaction is a crucial event.

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Karlsson, Jan Olof G., Per Jynge, and Louis J. Ignarro. "May Mangafodipir or Other SOD Mimetics Contribute to Better Care in COVID-19 Patients?" Antioxidants 9, no. 10 (October 10, 2020): 971. http://dx.doi.org/10.3390/antiox9100971.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by massive inflammation of the arterial endothelium accompanied by vasoconstriction and widespread pulmonary micro thrombi. As a result, due to the destruction of nitric oxide (•NO) by inflammatory superoxide (O2•−), pulmonary •NO concentration ceases, resulting in uncontrolled platelet aggregation and massive thrombosis, which kills the patients. Introducing •NO by inhalation (INO) may replace the loss of endothelium-derived •NO. The first results from clinical trials with INO in SARS-CoV-2 patients show a rapid and sustained improvement in cardiopulmonary function and decreased inflammation. An ongoing phase III study is expected to confirm the method’s efficacy. INO may hence become a first line treatment in SARS-CoV-2 patients. However, due to the rapid inactivation of •NO by deoxyhemoglobin to nitrate, pulmonary administration of •NO will not protect remote organs. Another INO-related pharmacological approach to protect SARS-CoV-2 patients from developing life-threatening disease is to inhibit the O2•−-driven destruction of •NO by neutralizing inflammatory O2•−. By making use of low molecular weight compounds that mimic the action of the enzyme manganese superoxide dismutase (MnSOD). The MnSOD mimetics of the so-called porphyrin type (e.g., AEOL 10150), salen type (e.g., EUK-8) and cyclic polyamine type (e.g., M40419, today known as GC4419 and avasopasem manganese) have all been shown to positively affect the inflammatory response in lung epithelial cells in preclinical models of chronic obstructive pulmonary disease. The Manganese diPyridoxyL EthylDiamine (MnPLED)-type mangafodipir (manganese dipyridoxyl diphosphate—MnDPDP), a magnetic resonance imaging (MRI) contrast agent that possesses MnSOD mimetic activity, has shown promising results in various forms of inflammation, in preclinical as well as clinical settings. Intravenously administration of mangafodipir will, in contrast to INO, reach remote organs and may hence become an important supplement to INO. From the authors’ viewpoint, it appears logical to test mangafodipr in COVID-19 patients at risk of developing life-threatening SARS-CoV-2. Five days after submission of the current manuscript, Galera Pharmaceuticals Inc. announced the dosing of the first patient in a randomized, double-blind pilot phase II clinical trial with GC4419 for COVID-19. The study was first posted on ClinicalTrials.gov (Identifier: NCT04555096) 18 September 2020.

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Lowes, Damon A., and Helen F. Galley. "Mitochondrial protection by the thioredoxin-2 and glutathione systems in an in vitro endothelial model of sepsis." Biochemical Journal 436, no. 1 (April 27, 2011): 123–32. http://dx.doi.org/10.1042/bj20102135.

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Oxidative stress and mitochondrial dysfunction are common features in patients with sepsis and organ failure. Within mitochondria, superoxide is converted into hydrogen peroxide by MnSOD (manganese-containing superoxide dismutase), which is then detoxified by either the mGSH (mitochondrial glutathione) system, using the enzymes mGPx-1 (mitochondrial glutathione peroxidase-1), GRD (glutathione reductase) and mGSH, or the TRX-2 (thioredoxin-2) system, which uses the enzymes PRX-3 (peroxiredoxin-3) and TRX-2R (thioredoxin reductase-2) and TRX-2. In the present paper we investigated the relative contribution of these two systems, using selective inhibitors, in relation to mitochondrial dysfunction in endothelial cells cultured with LPS (lipopolysaccharide) and PepG (peptidoglycan). Specific inhibition of both the TRX-2 and mGSH systems increased the intracellular total radical production (P<0.05) and reduced mitochondrial membrane potentials (P<0.05). Inhibition of the TRX-2 system, but not mGSH, resulted in lower ATP production (P<0.001) with high metabolic activity (P<0.001), low oxygen consumption (P<0.001) and increased lactate production (P<0.001) and caspase 3/7 activation (P<0.05). Collectively these results show that the TRX-2 system appears to have a more important role in preventing mitochondrial dysfunction than the mGSH system in endothelial cells under conditions that mimic a septic insult.

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Wing, Lih-Yuh Chen, Ya-Chi Chen, Yu-Yin Shih, Jung-Chien Cheng, Yiu-Jiuan Lin, and Meei Jyh Jiang. "Effects of Oral Estrogen on Aortic ROS-Generating and -Scavenging Enzymes and Atherosclerosis in apoE-Deficient Mice." Experimental Biology and Medicine 234, no. 9 (September 2009): 1037–46. http://dx.doi.org/10.3181/0811-rm-332.

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The effect of hormone replacement therapy (HRT) on cardiovascular diseases remains controversial. Studies conducted on postmenopausal women indicate that oral HRT increases risk factors that may counteract the atheroprotective effect of estrogen. However, the effects of estrogen on atherosclerosis have been examined using subcutaneous estrogen in most animal studies, which points to the need for evaluating the effect of oral estrogen. Reactive oxygen species (ROS) have emerged as critical factors in the pathogenesis of atherosclerosis. This study examined the effect of long-term oral estrogen treatment on aortic oxidative stress and atherosclerosis in female apoE−/− mice to mimic HRT in humans. Ovariectomized apoE−/− mice were given 6 μg/day of oral 17β-estradiol (E2) or control vehicle for 12 weeks. Estrogen treatment reduced atherosclerotic lesions by 38% (E2: 0.20 ± 0.01 mm2/section; control vehicle: 0.32 ± 0.02 mm2/section) and intima by 32% (E2: 0.44 ± 0.02 mm2/section; control vehicle: 0.65 ± 0.04 mm2/section) in the aortic root. Serum levels of total and low-density lipoprotein cholesterol were significantly decreased after estrogen treatment. Aortic superoxide anion levels and the expression of NAD(P)H oxidase subunit p22phox markedly decreased, and two ROS scavenging enzymes, Cu/ZnSOD and MnSOD, were upregulated after estrogen treatment. Estrogen at physiological concentration inhibited tumor necrosis factor-α-stimulated NAD(P)H oxidase activity in both cultured smooth muscle cells and peritoneal macrophages. These results showed that long-term oral estrogen treatment reduces ROS levels and atherosclerosis progression in apoE−/− mice. Oral estrogen alters ROS-generating and -scavenging enzyme expression, suggesting that anti-oxidative actions in the vessel wall contribute to atheroprotective effects of estrogen.

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Chaiswing, Luksana, Chontida Yarana, William St. Clair, Artak Tovmasyan, Ines Batinic-Haberle, Ivan Spasojevic, and Daret St. Clair. "A Redoxable Mn Porphyrin, MnTnBuOE-2-PyP5+, Synergizes with Carboplatin in Treatment of Chemoresistant Ovarian Cell Line." Oxidative Medicine and Cellular Longevity 2022 (May 9, 2022): 1–16. http://dx.doi.org/10.1155/2022/9664636.

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We have employed a redox-active MnP (MnTnBuOE-2-PyP5+, Mn(III) meso-tetrakis (N-n-butoxyethylpyridinium-2-yl) porphyrin) frequently identified as superoxide dismutase mimic or BMX-001, to explore the redox status of normal ovarian cell in relation to two ovarian cancer cell lines: OV90 human serous ovarian cancer cell and chemotherapy-resistant OV90 cell (OVCD). We identified that OVCD cells are under oxidative stress due to high hydrogen peroxide (H2O2) levels and low glutathione peroxidase and thioredoxin 1. Furthermore, OVCD cells have increased glycolysis activity and mitochondrial respiration when compared to immortalized ovarian cells (hTER7) and parental cancer cells (OV90). Our goal was to study how ovarian cell growth depends upon the redox state of the cell; hence, we used MnP (BMX-001), a redox-active MnSOD mimetic, as a molecular tool to alter ovarian cancer redox state. Interestingly, OVCD cells preferentially uptake MnP relative to OV90 cells which led to increased inhibition of cell growth, glycolytic activity, OXPHOS, and ATP, in OVCD cells. These effects were further increased when MnP was combined with carboplatin. The effects were discussed with regard to the elevation in H2O2 levels, increased oxidative stress, and reduced Nrf2 levels and its downstream targets when cells were exposed to either MnP or MnP/carboplatin. It is significant to emphasize that MnP protects normal ovarian cell line, hTER7, against carboplatin toxicity. Our data demonstrate that the addition of MnP-based redox-active drugs may be used (via increasing excessively the oxidative stress of serous ovarian cancer cells) to improve cancer patients’ chemotherapy outcomes, which develop resistance to platinum-based drugs.

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Miriyala, Sumitra, Ivan Spasojevic, Artak Tovmasyan, Daniela Salvemini, Zeljko Vujaskovic, Daret St. Clair, and Ines Batinic-Haberle. "Manganese superoxide dismutase, MnSOD and its mimics." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1822, no. 5 (May 2012): 794–814. http://dx.doi.org/10.1016/j.bbadis.2011.12.002.

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Greenberger, Joel S., Amitava Mukherjee, and Michael W. Epperly. "Gene Therapy for Systemic or Organ Specific Delivery of Manganese Superoxide Dismutase." Antioxidants 10, no. 7 (June 30, 2021): 1057. http://dx.doi.org/10.3390/antiox10071057.

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Manganese superoxide dismutase (MnSOD) is a dominant component of the antioxidant defense system in mammalian cells. Since ionizing irradiation induces profound oxidative stress, it was logical to test the effect of overexpression of MnSOD on radioresistance. This task was accomplished by introduction of a transgene for MnSOD into cells in vitro and into organs in vivo, and both paradigms showed clear radioresistance following overexpression. During the course of development and clinical application of using MnSOD as a radioprotector, several prominent observations were made by Larry Oberley, Joel Greenberger, and Michael Epperly which include (1) mitochondrial localization of either manganese superoxide dismutase or copper/zinc SOD was required to provide optimal radiation protection; (2) the time required for optimal expression was 12–18 h, and while acceptable for radiation protection, the time delay was impractical for radiation mitigation; (3) significant increases in intracellular elevation of MnSOD activity were required for effective radioprotection. Lessons learned during the development of MnSOD gene therapy have provided a strategy for delivery of small molecule SOD mimics, which are faster acting and have shown the potential for both radiation protection and mitigation. The purpose of this review is to summarize the current status of using MnSOD-PL and SOD mimetics as radioprotectors and radiomitigators.

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Clares, Ma Paz, Salvador Blasco, Mario Inclán, Lucas del Castillo Agudo, Begoña Verdejo, Conxa Soriano, Antonio Doménech, Julio Latorre, and Enrique García-España. "Manganese(ii) complexes of scorpiand-like azamacrocycles as MnSOD mimics." Chemical Communications 47, no. 21 (2011): 5988. http://dx.doi.org/10.1039/c1cc10526d.

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Schanne, G., M. Zoumpoulaki, S. Demignot, N. Delsuc, C. Policar, and P. Seksik. "P069 Design and delivery of anti-oxidant inorganic complexes mimicking the superoxide dismutase for inflammatory bowel diseases treatment." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i175—i176. http://dx.doi.org/10.1093/ecco-jcc/jjab232.198.

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Abstract Background Oxidative stress (OS), defined by an increased flux of reactive oxygen species (ROS), plays an important role in the pathogenesis, the perpetuation and the amplification of inflammatory bowel diseases. In normal state, enzymatic defenses regulate the concentration of ROS but in IBD, some of them, including the superoxide dismutase (SOD), are weakened. The use of molecules mimicking the SOD activity may compensate for this deficiency and reduce the OS. 4 molecules were characterized for their SOD activity, their stability and their inertness. Their anti-inflammatory activity were assessed in a cellular model of epithelial inflammation and in a murine model of colitis and correlated to their physico-chemical properties. Methods The studied SOD mimics display similar structures differing by the presence of a propyl and a cyclohexyle group aiming to improve their kinetic inertness. To generate an inflammation associated to ROS production, intestinal epithelial (HT29) cells were stably transfected to over-express MD2, a co-receptor for LPS binding to TLR-4 receptor. The cells were stimulated by LPS (0.1µg/mL) and incubated with the SOD mimics (6 hours, 0,1-100µM). The secretion of IL-8 was measured by ELISA and the MnSOD expression by Western Blot. The SOD mimics were administrated to a murine model of colitis chemically-induced by DNBS. To protect them from the gastric acidity, the mimics were encapsulated in delivery vector. The monitoring of weight and the determination of intestinal permeability and macroscopic scores were performed. Results The mimics containing a cyclohexyle group display kinetic rates for metal exchanges that are up to 30-fold lower meaning that they are more inert. At 100µM, the four SOD mimics induced a significative decrease in IL-8 secretion (<35%/positive control (PT), p<0,02) and in MnSOD expression (<20%/PT, p<0,033). At 10µM, only the mimics containing the cyclohexyle group are still able to significatively counteract the LPS-induced secretion in IL-8 (<30/PT, p<0,001) and over-expression of MnSOD (20%/PT, p<0,02). Their bioactivity at lower doses can be correlated to their higher inertness. Concerning in vivo activity, preliminary assays show a faster recovery of the mice, that have received the SOD mimics with the cyclohexyle group. 3 days following DNBS injection, the mice of this group recovered in average 89% of their starting weight while the control mice recovered only 83%. Conclusion The SOD mimics display anti-inflammatory and antioxidant activity on HT29-MD2 cells, which is dependent on their inertness. Assays on a murine model of colitis seems to follow the same trend. The use of antioxidant treatments based on SOD mimics may reduce the inflammation rising from oxidative stress in IBD.

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Huang, Hai-Feng, Fei Guo, Yuan-Zhao Cao, Wen Shi, and Qing Xia. "Neuroprotection by Manganese Superoxide Dismutase (MnSOD) Mimics: Antioxidant Effect and Oxidative Stress Regulation in Acute Experimental Stroke." CNS Neuroscience & Therapeutics 18, no. 10 (August 31, 2012): 811–18. http://dx.doi.org/10.1111/j.1755-5949.2012.00380.x.

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Lu, Zhuomin, Ian V. Lightcap, and Andrew G. Tennyson. "An organometallic catalase mimic with exceptional activity, H2O2 stability, and catalase/peroxidase selectivity." Dalton Transactions, 2021. http://dx.doi.org/10.1039/d1dt02002a.

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Valentino, Rosalin Bonetta. "The structure-function relationships and physiological roles of MnSOD mutants." Bioscience Reports, June 6, 2022. http://dx.doi.org/10.1042/bsr20220202.

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In this review, we focus on understanding the structure-function relationships of numerous manganese superoxide dismutase (MnSOD) mutants to investigate the role that various amino acids play to maintain enzyme quaternary structure or the active site structure, catalytic potential and metal homeostasis in MnSOD, which is essential to maintain enzyme activity. We also observe how polymorphisms of MnSOD are linked to pathologies and how post-translational modifications affect the antioxidant properties of MnSOD. Understanding how modified forms of MnSOD may act as tumor promoters or suppressors by altering the redox status in the body, ultimately aid in generating novel therapies that exploit the therapeutic potential of mutant MnSODs or pave the way for the development of synthetic SOD mimics.

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van der Slikke, Elisabeth C., Bastiaan S. Star, Matijs van Meurs, Robert H. Henning, Jill Moser, and Hjalmar R. Bouma. "Sepsis is associated with mitochondrial DNA damage and a reduced mitochondrial mass in the kidney of patients with sepsis-AKI." Critical Care 25, no. 1 (January 25, 2021). http://dx.doi.org/10.1186/s13054-020-03424-1.

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Abstract Background Sepsis is a life-threatening condition accompanied by organ dysfunction subsequent to a dysregulated host response to infection. Up to 60% of patients with sepsis develop acute kidney injury (AKI), which is associated with a poor clinical outcome. The pathophysiology of sepsis-associated AKI (sepsis-AKI) remains incompletely understood, but mitochondria have emerged as key players in the pathogenesis. Therefore, our aim was to identify mitochondrial damage in patients with sepsis-AKI. Methods We conducted a clinical laboratory study using “warm” postmortem biopsies from sepsis-associated AKI patients from a university teaching hospital. Biopsies were taken from adult patients (n = 14) who died of sepsis with AKI at the intensive care unit (ICU) and control patients (n = 12) undergoing tumor nephrectomy. To define the mechanisms of the mitochondrial contribution to the pathogenesis of sepsis-AKI, we explored mRNA and DNA expression of mitochondrial quality mechanism pathways, DNA oxidation and mitochondrial DNA (mtDNA) integrity in renal biopsies from sepsis-AKI patients and control subjects. Next, we induced human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS) for 48 h to mimic sepsis and validate our results in vitro. Results Compared to control subjects, sepsis-AKI patients had upregulated mRNA expression of oxidative damage markers, excess mitochondrial DNA damage and lower mitochondrial mass. Sepsis-AKI patients had lower mRNA expression of mitochondrial quality markers TFAM, PINK1 and PARKIN, but not of MFN2 and DRP1. Oxidative DNA damage was present in the cytosol of tubular epithelial cells in the kidney of sepsis-AKI patients, whereas it was almost absent in biopsies from control subjects. Oxidative DNA damage co-localized with both the nuclei and mitochondria. Accordingly, HUVECs induced with LPS for 48 h showed an increased mnSOD expression, a decreased TFAM expression and higher mtDNA damage levels. Conclusion Sepsis-AKI induces mitochondrial DNA damage in the human kidney, without upregulation of mitochondrial quality control mechanisms, which likely resulted in a reduction in mitochondrial mass.

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Brinck Teixeira, Rayane, Melissa Pfeiffer, Catherine Karbasiafshar, Giana Blume Corssac, Nagib Ahsan, Frank W. Sellke, and Ruhul Abid. "Abstract 17169: Endothelium-Specific Reduction in Mitochondrial ROS Induces Coronary Angiogenesis in Ischemic Myocardium via Activation of PI3k/Akt/ERG, ERK1/2, and Jag-1 Signaling." Circulation 142, Suppl_3 (November 17, 2020). http://dx.doi.org/10.1161/circ.142.suppl_3.17169.

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Introduction: Global reduction in reactive oxygen species (ROS) failed to improve outcomes in cardiovascular disease patients. Recent reports suggest that subcellular, rather than global ROS, play a crucial role in endothelial cell (EC) health. To that end, we generated a novel transgenic mouse model that overexpresses mitochondrial antioxidant MnSOD in EC-specific manner (MnSODVE-OE). Hypothesis: We hypothesized that decreased EC mitochondrial-ROS will improve post-myocardial infarction (MI) cardiac function by inducing coronary angiogenesis in ischemic myocardium. Methods: MnSODVE mice were assigned to Tet-ON (control) or Tet-OFF (MnSODVE-OE) group. To turn off the transgene, Tetracycline (Tet) (2mg/kg) was added to the drinking water (Tet-ON), while Tet-OFF mice did not receive Tet. Both groups underwent left anterior descending coronary artery (LAD) ligation surgery to mimic acute MI. Echocardiography was done 28 days after LAD ligation. Capillaries, arteriole density, and proliferating ECs were measured in heart sections using anti-CD31, anti-αSMA, and anti-PCNA immunofluorescence. Western blot, proteomic and phosphoproteomic analyses of mouse heart ECs isolated from MnSODVE (Tet-ON and Tet-OFF) animals were performed to study modulation of signaling cascades. Results: MnSODVE-OE mice demonstrated improved cardiac function (EF and FS increased by 16±7.87% and 21.73±10.31%, respectively, p <0.01), increase in capillary and arteriole densities by 4.13±4.10-fold, p<0.05 and 5.48±3.51-fold, p<0.001, respectively, and in EC proliferation by 1.46±0.80-fold, p <0.01, suggesting de novo coronary angiogenesis. Western blots showed activation of Akt (80.46±3.95% increase in p-Akt/ t-Akt ratio, p<0.05) and ERK1/2 (21.05±4.45% increase in p-ERK/ t-ERK 1/2 ratio, p<0.05). Proteome and phosphoproteome analyses showed upregulation of mitochondrial complex I biogenesis, RNA metabolism, and upregulation of Notch-related proteins ERG and Jag-1 (p<0.05). Student’s t-test was used for data analyses. Conclusions: Taken together, these results suggest that decreased mito-ROS in ECs improves post-MI cardiac function by inducing coronary angiogenesis through activation of PI3k/Akt/ERG, ERK1/2, and Jag-1 signaling.

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Al Haq, Aushia Tanzih, Hong-Yu Tseng, Li-Mei Chen, Chien-Chia Wang, and Hsin-Ling Hsu. "Targeting prooxidant MnSOD effect inhibits triple-negative breast cancer (TNBC) progression and M2 macrophage functions under the oncogenic stress." Cell Death & Disease 13, no. 1 (January 2022). http://dx.doi.org/10.1038/s41419-021-04486-x.

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AbstractTriple-negative breast cancer (TNBC) has been shown with high mitochondrial oxidative phosphorylation and production of reactive oxygen species (ROS). MnSOD (SOD2) is a mitochondrial antioxidant defense that has been implicated in inhibition of human malignancies. However, the impact of MnSOD on immunosuppressive macrophage functions and TNBC aggressiveness has never been explored. We found here that SOD2high is primarily observed in the aggressive subtypes of HER2(+) breast cancers and TNBCs patients. Further analyses demonstrated that the oncoprotein multiple copies in T-cell malignancy-1 (MCT-1 or MCTS1) induces mitochondrial superoxide dismutase (MnSOD) in TNBC cells by stabilizing the transcription factor Nrf2. SOD2high/MCTS1high expression correlates with a poor prognosis in breast cancer patients. MnSOD in TNBC cells functions as a prooxidant peroxidase that increases mitochondrial ROS (mROS) and adaptation to oxidative stress under the oncogenic effect. Interleukin-6 (IL-6) in the MCT-1 pathway elevates Nrf2/MnSOD and mROS levels. Knockdown of MnSOD inhibits TNBC cell invasion, breast cancer stem cells (BCSCs), mROS, and IL-6 excretion promoted by MCT-1. TNBC cells deficient in MnSOD prevent the polarization and chemotaxis of M2 macrophages but improve the ability of M1 macrophages to engulf cancer cells. Quenching mROS with MitoQ, a mitochondria-targeted non-metal-based antioxidant MnSOD mimics, effectively suppresses BCSCs and M2 macrophage invasion exacerbated by MnSOD and MCT-1. Consistently, silencing MnSOD impedes TNBC progression and intratumoral M2 macrophage infiltration. We revealed a novel stratagem for TNBC management involving targeting the MCT-1 oncogene-induced mitochondrial prooxidant MnSOD pathway, which prevents the development of an immunosuppressive tumor microenvironment.

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dos Santos Moura, Leila, Vinícius Santana Nunes, Antoniel A. S. Gomes, Ana Caroline de Castro Nascimento Sousa, Marcos R. M. Fontes, Sergio Schenkman, and Nilmar Silvio Moretti. "Mitochondrial Sirtuin TcSir2rp3 Affects TcSODA Activity and Oxidative Stress Response in Trypanosoma cruzi." Frontiers in Cellular and Infection Microbiology 11 (November 11, 2021). http://dx.doi.org/10.3389/fcimb.2021.773410.

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Trypanosoma cruzi faces a variety of environmental scenarios during its life cycle, which include changes in the redox environment that requires a fine regulation of a complex antioxidant arsenal of enzymes. Reversible posttranslational modifications, as lysine acetylation, are a fast and economical way for cells to react to environmental conditions. Recently, we found that the main antioxidant enzymes, including the mitochondrial superoxide dismutase A (TcSODA) are acetylated in T. cruzi, suggesting that protein acetylation could participate in the oxidative stress response in T. cruzi. Therefore, we investigated whether mitochondrial lysine deacetylase TcSir2rp3 was involved in the activity control of TcSODA. We observed an increased resistance to hydrogen peroxide and menadione in parasites overexpressing TcSir2rp3. Increased resistance was also found for benznidazole and nifurtimox, known to induce reactive oxidative and nitrosactive species in the parasite, associated to that a reduction in the ROS levels was observed. To better understand the way TcSir2rp3 could contributes to oxidative stress response, we analyzed the expression of TcSODA in the TcSir2rp3 overexpressing parasites and did not detect any increase in protein levels of this enzyme. However, we found that these parasites presented higher levels of superoxide dismutase activity, and also that TcSir2rp3 and TcSODA interacts in vivo. Knowing that TcSODA is acetylated at lysine residues K44 and K97, and that K97 is located at a similar region in the protein structure as K68 in human manganese superoxide dismutase (MnSOD), responsible for regulating MnSOD activity, we generated mutated versions of TcSODA at K44 and K97 and found that replacing K97 by glutamine, which mimics an acetylated lysine, negatively affects the enzyme activity in vitro. By using molecular dynamics approaches, we revealed that acetylation of K97 induces specific conformational changes in TcSODA with respect to hydrogen-bonding pattern to neighbor residues, suggesting a key participation of this residue to modulate the affinity to O2−. Taken together, our results showed for the first time the involvement of lysine acetylation in the maintenance of homeostatic redox state in trypanosomatids, contributing to the understanding of mechanisms used by T. cruzi to progress during the infection.

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Journal articles on the topic 'MnSOD mimic'

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