SFRBM dot SPRING 2012 • VOL. 4 • ISSUE 2

IN THIS ISSUE President's Message...... 2 THE VIEW Next FRS Webinar...... 3 Barry Halliwell, B.A., D.Phil., D.Sc. ˙ Research Forum...... 3 DOT: Tell us a little about your background and current passions Foundation Supports Young in your professional life. Investigators...... 4 Halliwell: I was born in a small town in the North of England, called Preston. A small textile town, it had a good football team (Preston Call for Nominations: Lifetime North End) and a large railway station, but not much else special. Achievement Award...... 8 Luckily for me, the local school system was excellent and I did well in both Humanities and Science. The Sciences won, and I obtained an Literature Review...... 9 exhibition (scholarship) to St. Catherine’s College−Oxford University, to study Biochemistry. The course, unlike many Biochemistry courses SFRBM at SOT...... 10 today, had a deep grounding in Chemistry, which I have found enor- mously useful in the free radical field. Some knowledge of Chemistry Barry Halliwell UPCOMING EVENTS helps one to challenge the alleged miraculous properties of certain “an- tioxidants” by showing that they have no chemical basis. FREE RADICAL SCHOOL WEBINAR In my final year at Oxford, I did a research project on plant science which inspired me so much Mitochondrial that I stayed on to do a D. Phil (Ph.D) in the Botany School, on plant metabolism during Processes photosynthesis, supported by St. Cross College. I mainly worked on photorespiration, the path- May 24, 2012 way that plants use to recycle 2-carbon compounds accidentally sent into the wrong metabolic

process when O2 instead of CO2 reacts with the first enzyme in the Calvin Cycle. It turned out that H2O2 plays an important role in photorespiration, and I learned that plant organelles read- ily make H2O2. After a period, I was then offered a junior academic position (lectureship) in a medical school (Kings College London) and switched my research largely to the role of free radicals and in human disease. However, I still have a soft spot for plants: they are

our source of life-giving yet poisonous O2 and of most diet-derived antioxidants. London and its environs was an excellent place to develop an interest in redox biology with such pioneers as Eric 19TH ANNUAL MEETING Wills, Tony Diplock and Trevor Slater being close at hand. My long-time colleague, John Gut- November 14 - 18, 2012 teridge, and I worked closely together to understand the in vivo role of hydroxyl radicals, and of Hilton San Diego Bayfront transition metal ions (especially iron) as catalysts of oxidative damage and how this contributes San Diego, CA USA to human diseases as diverse as atherosclerosis, dementia and cancer. We had little competition in this novel area: most researchers were focussing on superoxide as a directly-toxic species. SFRBM HEADQUARTERS During my academic career at King's College London, I was lucky enough to go on sabbatical to University of California−Davis, with considerable interaction with the Bruce Ames group at 8365 Keystone Crossing University of California, Berkeley. Working with Carroll Cross and his team at Davis, I was able Suite 107 to extend my research interests into how air pollutants interact with humans and other animals Indianapolis, IN 46240 to cause oxidative damage, an especially fruitful line of enquiry. This productive interaction con- 317/205-9482 tinued for many years even though it was only supposed to be a one-year sabbatical. fax: 317/205-9481 [email protected] Returning to King's, I received a Lister Institute Research Fellowship which freed me from www.sfrbm.org teaching to focus purely on research, again involving the role of free radicals and disease and in particular the development of new methods to detect oxidative damage in vivo, particularly to DNA. The Lister scheme was completely non-targeted, they picked scientists based on their

continued on page 7 SPRING 2012 SFRBM COUNCIL PRESIDENT'S MESSAGE President Harry Ischiropoulos, Ph.D. Harry Ischiropoulos, Ph.D. Children's Hospital of Philadelphia Research Institute University of Pennslyvania I trust that this message finds all members well Vice President of Research & as we are a quarter of the way through the New Scientific Development (President-Elect) Year. SFRBM’s leadership and committees have been Henry Forman, Ph.D. active on a number of projects, several of which I will University of California - Merced briefly report on here. Vice President of Finance We are in the final stages of planning our next Annual Margaret Briehl, Ph.D. Meeting, which will be held this November in sunny San University of Arizona Diego. Special thanks goes to our Program Committee, Vice President of Education & who evaluated innovative plenary session proposals Professional Development submitted by members. Featured symposia will include: Paul Brookes, Ph.D. University of Rochester • Redox Regulation of Cancer Metabolism Harry Ischiropoulos Vice President of Membership • Cellular Redox Sensors Sally Nelson, Ph.D. • Redox Lunchbox: What Your Gut is Telling You SomaLogic, Inc. • The Free Radical Theory of Aging Vice President of Communications • Enabling Technologies in Free Radical and Redox Research Chris Kevil, Ph.D. LSU Health Sciences Center Stay tuned for future details on invited speakers and prompts to submit your latest Past President research for oral or poster presentation at the meeting. Victor-Darley-Usmar, Ph.D. University of Alabama - Birmingham SFRBM is continuing fundraising efforts for our Foundation, with the express intent to support Travel and Young Investigator Awards as well as the association’s Executive Director Mini-Fellowship program. Please consider a donation to ensure valuable training Kent Lindeman, CMP opportunities for our future redox biology and researchers. Council Members Marcie Cole, Ph.D. Don’t forget about recognizing the contributions and achievements of our senior Brian Day, Ph.D. investigators as well. The nominations deadline for SFRBM’s Lifetime Achievement Rick Domann, Ph.D. Award is May 7. We encourage members to submit candidates for the Senior Award Neil Hogg, Ph.D. Committee’s consideration (see page 8 for more information). Eric Kelley, Ph.D. Alicia Kowaltowski, Ph.D. Aimee Landar, Ph.D. There are also new developments with our Journal,Free Radical Biology and Medicine. Francisco Laurindo, MD Many of you were aware of the charges of widespread scientific fraud that were Lee Ann MacMillan-Crow, Ph.D. leveled by the University of Connecticut against Dr. Dipak Das. The FRBM Ethics Lin Mantell, MD, Ph.D. Committee, chaired by Dr. Giovanni Mann, reviewed the allegations and, after Andre Melendez, Ph.D. following the proper protocols, has confirmed the findings of scientific fraud and Bulent Mutus, Ph.D. misconduct for 2 articles published in FRBM. They forwarded their findings to the Tim Oury, MD, Ph.D. FRBM Editor-in-Chief Dr. Kelvin Davies who has informed our publisher (Elsevier) Homero Rubbo, Ph.D. to formally retract these two articles. I appreciate the efforts of the Ethics Committee Sruti Shiva, Ph.D. for handling this most unfortunate case. Daret St. Clair, Ph.D. Albert van der Vliet, Ph.D. On a more positive note, I wanted to thank Anthony Newman and Elsevier for sponsoring awards recognizing the most prolific FRBM reviewers in 2011. Internal Marketing Committee Congratulations and many thanks to Drs. Dale Dickinson, Al Girotti, Neil Hogg, Dot Editor: Lee Ann MacMillian-Crow, Ph.D. Chris Kevil and Jacek Zielonka for their efforts and support to FRBM. We have Tak Yee Aw, Ph.D. also restructured the terms for FRBM’s Associate Editors that will allow increased Ines Batinic-Haberle, Ph.D. member opportunity to serve in these important positions. Christian Schöneich, Ph.D. Matthew Zimmerman, Ph.D.

continued on page 3 2 SOCIETY FOR FREE RADICAL BIOLOGY AND MEDICINE SPRING 2012

President's Message, continued from page 2 FREE RADICAL SCHOOL Finally, make sure to visit our website to view the latest posts to our Scientific Forum, watch an archived webinar (the latest is Dr. Dany Kim-Shapiro’s session on “Hemoglobin VIRTUAL SEMINAR SERIES Mediated NO Signaling”) or update your Member/ Research Directory profile. SFRBM offers virtual programming on a quarterly basis, providing valuable education on a wide range of topics. As always, please contact me with your suggestions, ideas The sessions are open to SFRBM members only and are and concerns. Thanks for your continued participation in offered at no charge. SFRBM. Mitochondrial Redox Processes Wednesday, May 30, 2012 LATEST POSTS IN 1:00 pm Eastern (17:00 GMT/UTC) Speaker: Alicia Kowaltowski, Ph.D. University of São Paulo RESEARCH FORUM Cost: FREE for SFRBM members In an effort to help in the exchange of information in our field, SFRBM has rolled out a new Research Forum as a PROGRAM OVERVIEW way to increase interaction and discussion among members. Mitochondria are a quantitatively relevant source of Members can post comments about methods, techniques or (ROS) in the majority of cell general questions for which they are looking for input from types. We will review the sources and metabolism of ROS colleagues. in this organelle, including the conditions that regulate the production of these species, antioxidant pathways, Here are the latest posts and discussions that can be found regulation of mitochondrial content and coupling. We on the Research Forum: will discuss substrate-, tissue-, and organism-specific characteristics of mitochondrial oxidant generation. Aging & Disease Several aspects of the physiological and pathological roles • Molecular mechanisms of epicatechin in the vasculature of mitochondrial ROS production will also be addressed. • Oxygen tension and Nox activity ABOUT THE SPEAKER Antioxidants and Novel Therapeutics Dr. Alicia J. Kowaltowski joined the Department of • Antioxidants and Antioxidant Treatment of Disease Biochemistry, University of São Paulo, Brazil in 2000, and is currently a full professor and coordinator of the Generation, Action & Metabolism of Reactive Species Graduate Program in Biochemistry. Her work focuses • A way to oxidize cell surface thiols on the interrelationship between mitochondrial energy • Changes in mt DNA and mitochondrial biogenesis metabolism, ion transport and redox state.

Cell and Systems Biology COST • Cocoa and enhanced mitochondrial function There is no cost for SFRBM members to participate. The • Palmitate on various cells and lipotoxicity webinar is open to SFRBM members only.

To stay up-to-date, sign up for the SFRBM Research Fo- rum Digest which summaries daily posts and replies within a single email. SFRBM members can access the Research Forum by logging in to the Members Only section of the SFRBM website and clicking on SFRBM Research Forum. LATEST ARCHIVED WEBINAR Hemoglobin Mediated NO Signaling SAVE THE DATE: SFRBM 2012 Speaker: Daniel Kim-Shapiro, Ph.D. See page 6 for featured sessions and more information. Wake Forest University Originally presented February 16, 2012 Visit the Members Only area at www.sfrbm.org.

WWW.SFRBM.ORG 3 SPRING 2012 SFRBM FOUNDATION SUPPORTS YOUNG INVESTIGATORS Interview by Jianhua Zhang, Ph.D.

The SFRBM Foundation is the charitable arm of SFRBM and supports our educational and training programs. The donations from our membership are absolutely critical and go towards fund- ing our Young Investigator Awards. Below we highlight the ex- perience of one our recent awardees and encourage you to help support this outstanding program!!

We interviewed one 2011 awardee, Brian Sansbury and his men- tor, Dr. Bradford Hill, for their perspective of the SFRBM confer- ence and what the Travel Award meant to them in their careers and pursuit of science.

Dr. Bradford Hill is an Assistant Professor in the Department of Cardiovascular Medicine at the University of Louisville. Brad won a SFRBM YIA as a postdoc in 2008. During a brief 2 year postdoctoral training, he published 9 manuscripts with his men- tor. Since becoming independent in 2009, he has kept up with Dr. Bradford Hill (left) and graduate student trainee Brian Sansbury his dynamite research rigor, creativity and productivity. He is (right). Brian's abstract on "Nitric Oxide Prevents Diet−Induced also an inspiring mentor as attested by one of his mentees; Brian Obesity by Regulating Adipose Tissue Phenotype" was selected for Sansbury has published 2 papers under Dr. Hill’s supervision and presentation during the Opening Session at SFRBM 2011. has obtained very exciting data on diabetes using mouse genetic models.

DOT: How important is the conference to you and your trainees?

Hill: Attending the SFRBM conference is a unique experience. Compared with other national meetings, I find it to be more stimulating, interactive, and educational. It is the only conference that I have found to consistently and effectively balance educa- tional and training experiences with cutting-edge science presented from leaders in the field. Personally, I have found the interface that occurs between attendees at poster sessions to be extraordinarily helpful, and I want all of my trainees to experience this as well. For example, just this year, I presented data from a project that had stalled. We were so stiflingly close to the project that we couldn’t distinguish a solution, i.e., we could not “see the forest for the trees.” The poster session gave me the opportunity to let the project “breathe” a bit, and I received suggestions and comments that have revived the work. For that, I am very thank- ful. I have also found the workshops to be extremely helpful. For example, Paul Brookes gave an overview of “How to Write the Training Plan of a Fellowship Application” this past year, which was of enormous help to me in developing Brian’s training plan for a predoctoral fellowship application. In my opinion, these qualities of the SFRBM meeting make it the “working model” for scientific conferences.

Sansbury: The SFRBM conference was an absolutely fantastic experience for me. I was given the opportunity to present our work and was really thrilled by the numerous responses, feedback and encouragement I received. The entire conference has a very cohesive feel and I immediately felt welcomed into the group. The meeting’s attendees seem to have a genuine interest in helping each other and want to become engaged with you and your work. This overwhelming sense of inclusion makes it easy to exchange ideas with each other and for a student or young investigator to meet established investigators to get valuable input or to discuss future opportunities. For example, on the final night of the conference, another student and I ran into Dr. Harry Is- chiropoulos, SFRBM President, outside the hospitality room. A simple “hello” wasn’t sufficient for him as he introduced himself and wanted to know all about our projects, our institutions and mentors, our experience at the conference and, of course, if we played soccer and what teams we followed. That type of genuine interest in one another, personally and professionally, regardless of career status, certainly made an impression on me and made me feel like I was welcome, that I belonged and that I was just as important as anyone else at the meeting. I think that is an extremely unique quality of the SFRBM conference as opposed to other national meetings.

4 SOCIETY FOR FREE RADICAL BIOLOGY AND MEDICINE continued on page 5 SPRING 2012

Foundation Supports Young Investigators, continued from page 4

DOT: From your perspective, how important are the SFRBM DOT: Do you have any advice for SFRBM junior faculties Travel awards to our junior scientists? What impact have and junior student/postdoc members who are preparing to you seen these awards make on the training experience of the compete for the 2012 Travel/YIA awards? awardee(s) you mentored? Hill: Yes. Spend time writing the abstract. Make sure it is the Hill: Brian is my first student, and, I, being a junior investiga- best it can be. This is especially important for the Travel Award tor, do not have much travel money to work with. Fortunately, because the abstract is the primary source from which the work his hard work over the past year was awarded with an SFRBM is judged. Also, if chosen for an oral presentation, it is impor- Travel Award, which allowed him to attend the meeting and tant to give a clear talk. If you do not deliver a clear presenta- present his research. I think Brian found the meeting to be re- tion, the chances of receiving a YIA will be nil. Short presenta- freshing and motivating. It gave him the opportunity to pres- tions typically take a longer time than expected to prepare; so ent his work in front of a relatively large audience and to have start early and practice often! SFRBM usually offers workshops in-depth discussions with other researchers working in or near on effective communication, and, commonly, the lecturers on the subject area. These types of experiences and interactions such topics will happily provide materials to assist in prepar- have been critical components to his training. ing for presentations. For example, last year a workshop on “How to Give an Effective Short Presentation” was available In addition, I think that the Sunrise Free Radical School ses- to attendees. In short, if the research is communicated well, it sions, a distinct characteristic of the SFRBM meetings, pro- will typically be received well and will have a better chance of vided Brian with a unique opportunity to become more versed receiving an award. in free radical biology. These sessions are especially useful if a trainee’s major is not related to biochemistry. Brian, for ex- Sansbury: Don’t be afraid to go for it. Even if the study has ample, is a student in the physiology program, and he has had holes or gaps or is incomplete, if there is an interesting finding little formal, structured learning in the area of free radical biol- and you are excited about the project, other people will find it ogy. Hence, these sessions have helped him “bridge the gap” interesting as well. Put an abstract together and make the story between his knowledge of physiology and biochemistry, which as complete and possible, then see how it is received. Don’t be has been useful in his ongoing dissertation project. overly dismissive of a project. If you believe in the study, sub- mit it and don’t be too afraid to give it a chance. The SFRBM conference should certainly be on the radar for anyone working in the free radical field. It is especially worth If your abstract gets accepted, there is no substitute for prepara- donating to the cause; in the end, it benefits everyone. tion. Practice your talk repeatedly; know exactly the message you want to send with each piece of data. It is impossible to an- Sansbury: I was very honored to receive a SFRBM Travel ticipate everything that may happen during a presentation, the award and am unsure if I would have been able to attend the only thing you have complete control over is your preparation. conference without it. Aside from the financial benefit of the Being sufficiently (or overly) prepared will make you more re- award, I also had the privilege to present our work during the laxed and will make your message clearer to the audience. opening session of the conference. In my experience, present- ing as often as possible is extremely beneficial. I can get so absorbed in the details of the project that taking a step back to put a story together in presentation (or poster) form helps Sunrise Free Radical me to reevaluate the progress we’ve made and what the next steps should be. It helps me to gather my thoughts and rein- School Webinars force the direction of the study. This presentation opportu- nity, specifically, was also of great benefit as I was able speak in front a crowd that was much larger than any other I have Visit the Members Only section at previously addressed. Getting this experience at an early stage www.sfrbm.org to view the latest archived of my development and becoming comfortable presenting data Sunrise Free Radical School Presentations and answering questions is very important as I hope to have from SFRBM's 18th Annual Meeting. the opportunity to present to many more large audiences in the future.

WWW.SFRBM.ORG 5 SPRING 2012 SFRBM NOVEMBER 14-18, 2012 HILTON SAN DIEGO BAYFRONT / SAN DIEGO, CA

19TH ANNUAL MEETING OF THE SOCIETY FOR FREE RADICAL BIOLOGY AND MEDICINE

ORAL PRESENTATIONS Plan to join us during & POSTER SYMPOSIA SFRBM’s Annual Meeting  Adaptative Responses  Biological Formation of Reactive Species to be held November 14-18  Biological Regulation by Reactive Oxygen Species  Cancer, Cell Proliferation and Death in San Diego, CA, USA  Cardiovascular Redox Biology and Pathology  Chemotherapy  DNA Damage and its Consequences  Free Radical Chemistry and Biochemistry FEATURED SESSIONS  Hydrogen Sulfide Chemistry and Biology   Redox Regulation of Cancer Metabolism  Inflammatory Oxidative Signaling and Injury  Lipids In Redox Biology  Cellular Redox Sensors  Macromolecule Modification  Mitochondria and Cell Proliferation  Redox Lunchbox: What Your Gut is Telling You  Nitric Oxide Chemistry, Biology and Physiology  Novel Therapeutics  The Free Radical Theory of Aging  Protective Enzymes (A Special Joint Symposium with the Gerontological Society of America)  Redox Imaging  Redox Signaling  Enabling Technologies in Free Radical Research  Redox Reaction Mechanisms  Signal Transduction and Gene Expression  Team Science: Integrating Multiple Perspectives  Superoxide and Superoxide Dismutases  Targeted Antioxidants  UV Effects and Atmospheric Pollutants

For further details regarding SFRBM 2012, please visit www.sfrbm.org and click on the SFRBM 2012 meeting logo. Questions about SFRBM 2012 can be directed to SFRBM via phone (317) 205-9482, fax (317)205-9481 or e-mail at [email protected].

6 SOCIETY FOR FREE RADICAL BIOLOGY AND MEDICINE SPRING 2012

The Radical View, continued from page 1 project and irrespective of its likely applicability. Nevertheless, the royalties made by Lister Fellows on patentable discoveries (es- pecially Alec Jeffreys’ DNA fingerprinting) were substantial, yet another demonstration of the value of investigator-led research. I must mention here my valuable collaboration with Miral Dizdaroglu, using the chemical techniques he pioneered to measure DNA oxidation products and applying them to biological samples to show the relevance of oxidative DNA damage to human disease.

In June 1998, I went on another sabbatical, to the National University of Singapore (NUS). This time, I never went back to London and am still in Singapore but contemplating yet another sabbatical (perhaps a dangerous thing to do!). Singapore is a remarkable place, dedicated to investment in education and research, which has helped transform this small country with no natural resources into an economic powerhouse. My own research there flourished, and I had the privilege of working alongside two excellent University Presidents in helping to steer NUS from being a well-regarded but rather staid teaching University into a serious player in the world research leagues, over a wide range of disciplinary and inter-disciplinary areas. I have been Deputy President, in charge of research and technology, for almost five years now. Hard work, but its exhilarating to see research quality and quantity getting rapidly better, and in some areas already among the best in the world.

My current passions are to find novel and interesting research areas related to preventing dementia and understanding ageing, as well as to help develop NUS from a top 40 to a top 20 University.

DOT: What made you decide to be a scientist and what are the important factors that shaped your career?

Halliwell: I came from a “working class” background but was lucky in my parents – they had an enormous belief in education as an avenue of social mobility, and I was lucky to be able to attend Preston Grammar School – a state school that had teaching staff equivalent in quality to that of many leading private schools (the British call them “public schools”). This passion for quality education has drained away somewhat in the UK (sadly) but is still strongly evident in Asia (and in Asians, wherever they may be) today. The curriculum was broad-based and I enjoyed many subjects, eventually picking the sciences to study at University. I toyed with the idea of doing Medicine and in retrospect I probably should have since the opportunities for clinician-scientists are enormous now, but this was not a recognized career pathway then in the UK.

DOT: What was your most exciting discovery in research?

Halliwell: I still feel a sense of excitement when a set of previously-incomprehensible data suddenly begins to make sense, and an experiment at last gives the result that you predicted. My first Ph.D. student, , and I elucidated the ascorbate- cycle (Halliwell-Foyer-Asada cycle), a novel pathway used by chloroplasts to remove H2O2. Work by Groden, Beck and Asada helped us to firm up the details. The pathway has now taken on a new importance because genetic manipulation of its activity can help crops resist environmental changes.

I am also proud of our work on the role of iron in free radical reactions, our unequivocal demonstration of the formation of hydroxyl radicals in vivo, and our developing methods to detect free radicals and oxidative damage in human material. It was apparent to me early on that while many researchers in the field were speculating on a role for oxygen radicals and other reactive oxygen species (ROS) in human disease and assuming that high doses of nutritional antioxidants would scavenge these radicals and delay disease onset, the methods required to measure ROS and (probably more importantly) the biological damage that they cause in vivo were inadequate. We applied a number of methods, from aromatic hydroxylation to urate degradation and ‘finger- printing’ of oxidative DNA damage (with Miral), which have become widely used. The question of whether free radicals really do play an important role in human disease pathology is still an open one for most diseases, although I am convinced that they are important in neurodegeneration, and cancer, and the former is one focus of my current work. Most recently, we are studying the free radical theory of ageing using C.elegans as a model: the results are weird and wonderful. This simple nematode seems to be a useful model for frailty in humans, and a good testbed for strategies to help delay age-related disability.

In a “negative” sense, our work showing how artefacts in cell culture can seriously mislead researchers in the antioxidant/poly- phenol field is a simple example of how failure to consider the basic chemistry of cell culture media (rapidly fluctuating O2 levels – often hyperoxic, abnormal chemical environment, strong pressure for rapid adaptation to the cell culture environment causing genetic changes) can lead scientists astray. The work is simple (largely conducted by Lee Hua Long, a very able laboratory tech- nologist under my direct supervision), yet the implications are profound. continued on page 8

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The Radical View, continued from page 7

students, post-docs, academics etc) who had the same research DOT: How has science/research changed during your life problems as you, and sometimes a solution! It felt good as my as a scientist? research developed to be sometimes able to offer help to others working on entirely different projects. Halliwell: Almost every method I learned in my BA and D.Phil. studies is now obsolete, as is most of the informa- Such advice is particularly important for Singapore – it has been tion (although not the fundamental chemistry) I learned too easy in Asia to repeat and extend what has been done in the from my lectures and tutorials. Perhaps the most useful skill west. My great pleasure at the moment at NUS is to watch the I obtained at University, through the Oxford tutorial sys- rise of science; in some areas NUS is now in a leading position tem, was that of good communication, both verbally and in globally and forging its own path. writing (write a short essay, write it again until the tutor is satisfied), together with the ability to dig out and marshall facts from the literature (pre-Google, pre-Yahoo, and pre- PubMed!). One thing that worries me now is that people rely too much on kits and published “protocols”, without enquiring how these things actually work and can they really CALL FOR NOMINATIONS do what they promise. Often methods are relegated to “sup- 2012 Lifetime Achievement Award plementary material” in papers, as if they mattered little. Deadline: May 7, 2012 There is too much “kitology research” in the redox biology field already, and it seems to be growing. SFRBM is now calling for nomina- Nonetheless, methodological advance has been enormous tions from members for the 2012 and is beginning to reveal the true complexity behind such Lifetime Achievement Award. This vague terms as “oxidative damage” – what is damaged, award recognizes an aggregate body where, and how much – and what is the biological impact at of work important to the field of free the molecular level? The omics have helped enormously, al- radical chemistry, redox biology and though proteomics, genomics and lipidomics are still prone antioxidants over a scientist's career. to methodological artefacts that need careful consideration. This award will include a featured lecture at SFRBM's 19th DOT: What advice would you give to young researchers entering the field? Annual Meeting in San Diego, CA USA as well as:

Halliwell: First, pick the right lab for your Ph.D. and post- • $2,500 cash award doctoral research. The PI could be new and upcoming or • Paid travel expenses to SFRBM 2012 older and established, but make sure they are at the cut- ting edge of whatever field you are interested in. If older • A bronze medal with stand and established, do they actually spend time with students? Choose an important project that will get you excellent • Invited to publish a review article for Free Radical papers if it works, plus a couple of sub-projects related to Biology & Medicine, SFRBM’s journal, celebrating their ongoing work that are more likely to deliver good results. scientific contributions and the presentation of the Learn by attending seminars (even if outside your field), award discussion groups, conferences and lab meetings. Take op- portunities to showcase your work at major international • Have a one page bio and picture prominently displayed meetings and learn from the suggestions/criticisms made in the SFRBM 2012 Abstract/Program book. by the international research community. It’s not only the supervisor who matters, find out how well the post-docs, Nominations for the Lifetime Achievement Award will graduate students and technicians in the research group and be taken through May 7, 2012. For more information Department interact – you may learn far more from them. Make friends with graduate students from other labs and regarding nominations please visit: institutions. During my D. Phil. at Oxford, it was expected http://sfrbm.org/sections/senior-awards.php that everyone in the Department attended afternoon tea several days a week. Originally, I thought this was an irrita- tion as I had to plan experiments around it. I soon learned its value – you chatted purely by accident to people (other

8 SOCIETY FOR FREE RADICAL BIOLOGY AND MEDICINE SPRING 2012

LITERATURE REVIEW

Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin. Patti GJ, Yanes O, Shriver LP, Courade J-P, Tautenhahn R, Manchester M, Siuzdak G, Nature Chemical Biology (2012), doi:10.1038/nchembio.767.

Neuropathic pain is a debilitating condition for which the development of effective treatments has been limited by an incomplete understanding of its chemical basis, although inflammation and oxidative stress have been implicated in its development. To investigate the chemical basis of neuropathic pain, the authors performed MS-based metabolomics on Sprague-Dawley rats suf- fering from tibial nerve transection (TNT), a well-established model of neuropathic pain that induces allodynia, a condition in which normally innocuous stimuli elicit a pain response. Specifically, their investigation was focused on the metabolic alterations in the spinal cord during the later stages of neuropathic pain, showing that N,N-dimethylsphingosine (DMS), a endogenous ceramide metabolite that has not been previously implicated in nociception, induces pathological responses in the dorsal spinal cord that are associated with the development of pain behaviors and that the mechanism by which DMS mediates mechanical allodynia may occur via production of inflammatory mediators such as interleukin-1β (IL-1β) or monocyte chemoattractant protein-1 (MCP-1) in the CNS. Authors further suggest that inhibition of endogenous DMS production, with a methyltrans- ferase or ceramidase inhibitor, for example, may be an attractive therapeutic candidate to treat this debilitating condition. It may also be worthwhile noting that ceramide is a sphingolipid with powerful proapoptotic and proinflammatory properties and has been previously implicated in oxidative/nitrosative stress. Ceramide is generated by enzymatic hydrolysis of sphingomyelin by sphingomyelinases (the so-called sphingomyelin pathway) and is well established as a major proapoptotic mediator following ra- diation, chemotherapeutics, or exposure to proinflammatory cytokines, including TNF-α, IL-1β, IL-6, and oxidative/nitrosative stressors, whereby NF-κB and AP-1 pathways are involved. The increased formation of ceramide promotes oxidative/nitrosative stress and enzymatic inactivation of MnSOD, thereby triggering apoptosis. Therefore, the mediation of redox-based pathways may also be a valid approach to alleviate chronic neuropathic pain. Prepared by Tin Weitner and Ines Batinic-Haberle, Duke University Medical Center.

Antioxidant and Oncogene Rescue of Metabolic Defects Caused by Loss of Matrix Attachment. Zachary T. Schafer, Alex- andra R. Grassian, Loling Song, Zhenyang Jiang, Zachary Gerhart-Hines, Hanna Y. Irie, Sizhen Gao, Pere Puigserver, and Joan S. Brugge. Nature 461, 109-113, 2009.

Normal epithelial cells are dependent on interactions with specific extracellular matrix (ECM) components for survival, prolif- eration and differentiation functions. The ability of tumor cells to survive outside their natural ECM niches is dependent on the acquisition of anchorage independence. Apoptosis is the most rapid mechanism for eliminating cells lacking appropriate ECM attachment. In the paper the authors have demonstrated that detachment of mammary epithelial cells from ECM causes an ATP deficiency due to the loss of glucose transport. Overexpression of ErbB2 rescues the ATP deficiency by restoring glucose uptake through stabilization of EGFR and PI(3)K activation and this rescue is dependent on glucose-stimulated flux through the antioxidant-generating pentose phosphate pathway. They have found that the ATP deficiency could be rescued by antioxi- dant treatment without rescue of glucose uptake. This rescue was found to be dependent on stimulation of fatty acid oxidation, which is inhibited by detachment-induced reactive oxygen species (ROS). The significance of these findings was supported by the evidence of an elevation in ROS levels in matrix-deprived cells in the luminal space of mammary acini, and by the fact that antioxidants facilitate the survival of these cells and enhance anchorage-independent colony formation. These results reveal both the importance of matrix attachment in regulating metabolic activity and an unanticipated mechanism for cell survival in altered matrix environments through antioxidant restoration of ATP generation. Intriguingly, these data demonstrate that anti- oxidants promote the survival of cells that lack attachment to the ECM and raise the question whether antioxidants may have dichotomous activities with respect to tumorigenesis(1) suppressing tumorigenesis by preventing oxidative damage to DNA; and (2) promoting tumorigenesis by allowing survival of cells that are metabolically impaired (e.g. in altered matrix environments). Prepared by Artak Tovmasyan and Ines Batinic-Haberle, Duke University Medical Center.

continued on page 10

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Literature Review, continued from page 9

Autophagy proteins LC3B, ATG5 and ATG12 participate in quality control after mitochondrial damage and influence life span. Sören Mai, Britta Muster, Jürgen Bereiter-Hahn and Marina Jendrach. Autophagy 8:1, 47–62; January 2012; G 2012 Landes Bioscience.

Mitochondrial quality control is essential for cellular function and survival. Mitochondrial-targeted phototoxicity by irradiation of HUVEC cells led to transient fragmentation of mitochondria followed by mitophagy, with associated upregulation of LC3B, ATG5, ATG12, and PGC1α. Increased expression of LC3B, ATG5 and ATG12, but neither LAMP-1 nor ATG1, enhanced replicative life span up to 150%. So what are the mechanisms underlying the life span enhancement? First, the enhancements of life span by these autophagy proteins were associated with an improved mitochondrial membrane potential and enhanced ATP production, suggesting mitochondrial quality is associated with life span. Second, LC3B overexpressing cells also exhibit de- creased mtDNA damage. However, ROS levels (as measured by DHE) remained unchanged and the amount of oxidized proteins was slightly but not significantly increased. Although further studies are in need, the authors attributed the lack of global effect of increasing autophagy proteins on ROS or oxidized proteins to a redistribution of ROS and oxidized proteins. Third, although overexpressing LAMP-1 does not enhance replicative life span, it does protect cells against -induced apoptosis, a phenomenon shared by overexpression of LC3B, ATG5, or ATG12 in HUVEC cells. This evidence suggested that increased autophagy may enhance life span by a mechanism independent of protection against apoptosis. Fourth, in already senescent cells, enhanced expression of autophagy proteins did not affect mitochondrial membrane potential, or ROS, suggesting that senescence is irreversible by autophagy proteins. Whether enhanced expression of autophagy proteins can further life span in senescent cells have not been measured in this study. This study supports a role of specific autophagy proteins in enhancing life span, via mecha- nisms that may involve improved mitochondrial membrane potential, enhanced ATP production, and decreased mtDNA damage. Prepared by Jianhua Zhang, University of Alabama at Birmingham. A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Soubannier V, McLelland GL, Zunino R, Bra- schi E, Rippstein P, Fon EA, McBride HM. Curr Biol. 2012 Jan 24;22(2):135-41. Epub 2012 Jan 5.

Mitochondrial quality control is essential for cell function and survival. Mitochondrial quality has been shown to be high- ly regulated both by the fission/fusion machinery and by the autophagy of mitochondria (mitophagy) pathway that turn- over dysfunctional or damaged mitochondria. Up till recently, it was unclear whether any other pathways exist that may be able to exert similar functions. McBride and colleagues recently identified mitochondria-derived vesicles (MDVs) that con- tain an outer-membrane mitochondria-anchored protein ligase (MAPL), but not DRP1 or TOM20. In this article, the au- thors observed that treating cells with several reactive oxygen species generating agents, including glucose oxidase to HeLa cells, xanthine oxidase/xanthine to COS cells grown in galactose, or antimycin A, increased mitochondria-derived vesicles (MDV). N-acetyl-cysteine (NAC) decreased the MDV accumulation. Delivery of MDVs to the lysosomes does not require mitochondrial depolarization, and is independent of autophagy proteins, ATG5 and LC3, and does not require fission pro- tein DRP1. Comparing to mitophagy, the generation of MDVs occurs directly from the lateral segregation of cargo into budding vesicles that appear along the tubule of a respiring, functional mitochondrion. What are the signaling pathway to differentiate which parts of the mitochondria are to form the MDVs have not been determined. It was hypothesized to in- volve protein or lipid oxidation. This is an interesting work pointing to novel mechanisms of mitochondrial quality control. Prepared by Jianhua Zhang, University of Alabama at Birmingham.

SFRBM Exhibits at the Society of Toxicology (SOT) San Francisco, CA March 12 - 14, 2012 A primary Membership Recruitment committee goal is to reach out to other societies where there exists considerable overlap in scientific pur- suits in order to expose/advertise SFRBM and recruit new members. Accomplishment of this goal will serve to augment exposure of SFRBM to colleagues from related fields as well as enhance membership and maximize the potential for mutually beneficial professional networking. To assist with obtaining this goal, SFRBM was a first-time exhibitor at the Society for Toxicology (SOT) Annual Meeting in San Francisco, CA, March 12 - 14, 2012. We spoke to over 100 SOT attendees, and as SFRBM members, Drs. Marcelo Bonini (left) and a result, signed up over 35 new SFRBM members. Maria Kadiiska (right) at the SFRBM Exhibit Booth.

10 SOCIETY FOR FREE RADICAL BIOLOGY AND MEDICINE