
Al W. Girotti, PhD
Professor
Locations
- Biochemistry
BSB 359
Contact Information
Biography
Dr. Girotti received his Bachelor of Science degree in Biology from Massachusetts Institute of Technology in 1959 and his Doctorate degree in Biochemistry from the University of Massachusetts, Amherst in 1965. He was a Postdoctoral Research Associate at Cornell University Medical College (1965-1968) where he investigated the role of metal ions in ribonuclease activity. Dr. Girotti joined the faculty of the Biochemistry Department at the Medical College of Wisconsin in 1968.
Education
PhD, University of Massachusetts, Amherst, 1965
BS, Massachusetts Institute of Technology, 1959
Research Interests
Aerobic cells may experience oxidative stress damage if their enzymatic and non-enzymatic antioxidant defenses are overwhelmed by reactive oxygen species (ROS) generated by various endogenous and exogenous challenges. Unsaturated lipids in cell membranes and lipoproteins are prominent targets of ROS attack, undergoing peroxidative degradation with numerous structurally and functionally disruptive effects. Examples of free radical and non-radical ROS are shown in Scheme 1.
Among the many intermediates/products of lipid peroxidation, hydroperoxide species (LOOHs) are of special interest because of their relatively long lifetimes compared with free radical precursors or products. Under redox-constrained conditions, LOOHs can accumulate steadily with stress duration and may perturb membrane structure/function because of their relatively polar nature. However, in the presence of reductants and catalytic iron, LOOHs can undergo one-electron reduction with formation of oxyl (LO·) and epoxyallylic peroxyl (OLOO·) radicals, which exacerbate membrane damage by triggering chain peroxidation reactions (Scheme 1). Counteracting this is two-electron reductive detoxification catalyzed, for example, by glutathione-dependent selenoperoxidases, GPx4 (also known as PHGPx) being the most prominent isotype. Other LOOH pathways include inter-lipid transesterification and inter-membrane or membrane-lipoprotein translocation.
The Girotti group specializes in LOOH formation, turnover, and redox signaling activity, the latter currently attracting widespread biological and biomedical interest. Relatively low LOOH pressure may signal for upregulation of antioxidant proteins and activation of pro-growth transcription factors, whereas high LOOH pressure can signal for growth cessation and programmed cell death (apoptosis). Ongoing projects in the Girotti laboratory include the following: (a) Selenoperoxidase-mediated LOOH metabolism and how this modulates the pathologic as well as therapeutic effects of oxidative stress - as in antitumor photodynamic therapy (PDT), for example; (b) the biological ramifications of spontaneous or transfer protein-facilitated LOOH translocation between membranes or membranes and lipoproteins; pioneering studies of this phenomenon were carried out in the Girotti laboratory; (c) Protective effects of nitric oxide (NO) against cancer cell killing by PDT. Depending on its generation rate and location in cells, nitric oxide synthase (NOS)-derived NO can either be cytotoxic or cytoprotective (Scheme 2). In the latter category, our work has revealed that NO can (i) scavenge lipid-derived free radicals, (ii) induce antioxidant proteins such as heme oxygenase-1 and ferritin, or (iii) engage pro-survival/pro-growth signaling pathways that can compromise the effectiveness of PDT.
Publications
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Is Photodynamic Therapy Resistance a Special Case of Photobiomodulation?
(Quirk BJ, Girotti AW, Whelan HT.) Photomed Laser Surg. 2018 08;36(8):397-398.
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Cholesterol Peroxidation as a Special Type of Lipid Oxidation in Photodynamic Systems.
(Girotti AW, Korytowski W.) Photochem Photobiol. 2019 Jan;95(1):73-82.
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Upregulation of nitric oxide in tumor cells as a negative adaptation to photodynamic therapy.
(Girotti AW.) Lasers Surg Med. 2018 Jul;50(5):590-598.
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(Fahey JM, Stancill JS, Smith BC, Girotti AW.) J Biol Chem. 2018 04 06;293(14):5345-5359.
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Bystander effects of nitric oxide in anti-tumor photodynamic therapy.
(Bazak J, Fahey JM, Wawak K, Korytowski W, Girotti AW.) Cancer Cell Microenviron. 2017;4(1).
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Cholesterol Hydroperoxide Generation, Translocation, and Reductive Turnover in Biological Systems.
(Girotti AW, Korytowski W.) Cell Biochem Biophys. 2017 Dec;75(3-4):413-419.
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Bystander effects of nitric oxide in anti-tumor photodynamic therapy
(J. Bazak, J.M. Fahey, K. Wawak, W. Korytowski, A.W. Girotti.) Cancer Cell Microenvironment. 4:e1511.doi:10.14800/ccm.1511.
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(Fahey JM, Girotti AW.) Nitric Oxide. 2017 Jan 30;62:52-61.
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(Bazak J, Fahey JM, Wawak K, Korytowski W, Girotti AW.) Free Radic Biol Med. 2017 01;102:111-121.
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Multiple Means by Which Nitric Oxide can Antagonize Photodynamic Therapy.
(Girotti AW, Fahey JM, Korytowski W.) Curr Med Chem. 2016;23(24):2754-2769.
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Modulation of the Anti-Tumor Efficacy of Photodynamic Therapy by Nitric Oxide.
(Girotti AW.) Cancers (Basel). 2016 Oct 20;8(10).
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Antagonistic Effects of Endogenous Nitric Oxide in a Glioblastoma Photodynamic Therapy Model.
(Fahey JM, Emmer JV, Korytowski W, Hogg N, Girotti AW.) Photochem Photobiol. 2016 11;92(6):842-853.