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An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins

Click here to view the complete article in Redox Biology

Most of the SOD mimics thus far developed belong to the classes of Mn-(MnPs) and Fe porphyrins(FePs), Mn(III) salens, Mn(II) cyclic polyamines and metal salts. Due to their remarkable stability we have predominantly explored Mn porphyrins, aiming initially at mimicking kinetics and thermodynamics of the catalysis of O2− dismutation by SOD enzymes. Several MnPs are of potency similar to SOD enzymes. The in vivo bioavailability and toxicity of MnPs have been addressed also.

Numerous in vitro and in vivo studies indicate their impressive therapeutic efficacy. Increasing insight into complex cellular redox biology has been accompanied by increasing awareness of complex redox chemistry of MnPs. During O2− dismutation process, the most powerfulMn porphyrin-based SOD mimics reduce and oxidize O2− with close to identical rate constants. MnPs reduce and oxidize other reactive species also (none of them specific to MnPs), acting as reductants (antioxidant) and pro-oxidants.

Distinction must be made between the type of reactions of MnPs and the favorable therapeutic effects we observe; the latter may be of either anti- or pro-oxidative nature. H2O2/MnP mediated oxidation of protein thiols and its impact on cellular transcription seems to dominate redox biology of MnPs. It has been thus far demonstrated that the ability of MnPs to catalyze O2−dismutation parallels all other reactivities (such as ONOO− reduction) and in turn their therapeutic efficacies.

Assuming that all diseases have in common the perturbation of cellular redox environment, developing SOD mimics still seems to be the appropriate strategy for the design of potent redox-active therapeutics.

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Categories: Education, Redox Biology


Alternate Careers and Networking: It is the Ruby Slippers - You’ve had the Ability all Along

By: Kelly K. Andringa, PhD, MBA, University of Alabama at Birmingham Division of Nephrology Program Manager

As Michelle mentioned last month you don’t want to be nearing the finish with your postdoc (or perhaps even your graduate training) without having a career goal or target in mind. These goals and targets can change, but you should have some idea where you’d like to start. Sometimes these goals aren’t the same as your mentors and you might not have any idea exactly how to get where you want to go. This is where you need an active network (something else Michelle mentioned) to help you out. 

Networking is discussed ALL the time as the vital part of any career path, not just science. If your career aspirations take you away from the traditional academic faculty track you will need to reach out and talk to others who have those roles you’re interested in. “Alternate careers” is a phrase that gets thrown around a lot. The statistics about obtaining an academic faculty position look daunting (see this video from Dr. Sally Rockey about the average age of faculty and R01 PIs in academia over the last 20+ years) and lead people to think about exploring other options. Now, let me be clear, I thoroughly enjoy my “alternate career,” it is in no way my “back up plan.” I haven’t taken the positions I have after my postdoc because I was discouraged from being faculty, I went into this career path fully aware of what I was getting into and what I was giving up. I definitely think that careers in academic research are possible and people who want them should absolutely go for them. I am not that person.

During my graduate training I had 5 projects going, I needed a bit of help narrowing my focus. About the time of my qualifying exams, my mentor and I had a good sit down about my career goals and aspirations. Although I had initially gone to graduate school with the goal of running my own lab and working on more tolerable therapeutics for cancer treatment, I had started to realize I had skill sets that would be better utilized outside the lab. Fortunately, my graduate and postdoctoral mentors were open to those discussions about careers outside of academic faculty positions. Thankfully, I’m reasonably willing to talk about the things I want/need regardless of the outcome, but not everyone has mentors that are supportive of other career paths. Luckily, Science Careers (sponsored by AAAS) has an online IDP (Individual Development Plan) to help you determine your interests and get them down ‘on paper’ so you have a career plan going forward that you can modify and discuss.

Clearly, there are a number of “alternate careers” out there and I’m hoping there will be more blog posts about some of the other ways people utilize their PhD’s outside of academia. I can only speak to my area of interest, I’m in Research Administration. What do I do every day?? Well my daily tasks are varied and no day is the same. I’m currently a Program Manager at the University of Alabama at Birmingham. I assist in the management of a multi-institution P30 grant that has three research areas with about 7 different core facilities involved with those areas. There is also a pilot grant program as well as educational components for seminars, workshops and training experiences. I also assist in the management of an NRSA postdoctoral training grant that currently funds 5 trainees, plus a number of other tasks for my boss and my division. Here is what I enjoy most about my job; I get to talk about all different kinds of science and research with so many different people. I help direct faculty interested in utilizing our core facilities to the correct people, I get to read about new and exciting research directions via the pilot studies proposed, and watch young scientists transition their careers where they want to go, it’s great. I do miss the bench work, but I think my skills are best utilized in helping others reach their scientific research goals.

So how did I get here? We have to take it back to networking, as Glinda told Dorothy; you’ve had the ability all along you just wouldn’t have believed me. In those original discussions with my graduate mentor, he mentioned that one of his classmates from graduate school was a program officer at NIH. He sent her an email asking if she would be willing to talk to me about her career and what her job entailed. Here’s a hint, informational interviews are a great way to connect with people who have jobs you’re interested in. This is not a time to pester them to get you a job or pass around your CV, this is informational, you are inquiring about their job, how they got there and what they do on a daily basis. I sent a number of emails and had friends send emails to people who had jobs I was interested in learning about. I talked to program officials at NIH, associate vice presidents of small and large universities, directors of sponsored programs, program managers from my university and others in compliance offices (IRB, IACUC etc.) about their jobs. Networking is important, don’t be pushy, and ask when a good time is to call. Have a number of questions ready but don’t plan to take up more than 30 minutes of their time (maybe less), they can make it go longer but you shouldn’t be the one keeping them on the phone for hours, they’re busy and you want them to remember you were sensitive to their time.

So you’re likely thinking, great advice Kelly, but does it really work? In fact yes, it does work. One of those informational interviews I had was with someone who also had transitioned from a postdoc to grants management. A year after I spoke with her, her division was looking for someone to manage and ARRA funded multi-site project. She contacted me to see if I was still interested in administration and if I would like to interview for the job. So see, making a good impression while learning about someone else’s job got me an “in” for an interview. Networking won’t necessarily get you the job. Your education, training, and knowledge will get you the job; networking can help get you in the door.

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Category: Education


The 5 Rules of Career Success for a Young Scientist

By: Michelle Booze, Postdoctoral Fellow, Children’s Health Research Center at Sanford Research - @DrMLBooze, @sanfordhealth

This past March I had the opportunity to attend the National Postdoctoral Association (NPA) 2015 Annual Meeting. What I learned there helped me to focus on my future as a scientist. Are you getting the career help you need to determine your future? Luckily, there is a wealth of information out there to help you along your journey. The following are 5 rules to get you started down the right path to your dream career.

Rule #1: Don’t be this person

This information was presented by Sarah Cardozo-Duncan (@sarahcarstrat) and James Gould (@HMSpostdoc) during a workshop at the meeting. It is important not to be the person who:

  1. Is near their end date before they think about their future
  2. Is unsure of what marketable skills they have
  3. Has an inactive network
  4. Has little or no mentor engagement
  5. Has an unknown career target or goal
  6. Has an unpolished career story
  7. Has unreal expectations

Rule #2: Know what you want to do with your degree

It is very important that you take time to think about where you want to be in your future. It’s never too late to figure this out and start pursuing your goal. Don’t set unrealistic goals, but don’t hold back either or you might not reach your full potential!

Rule #3: Find a valuable mentor

If you want your PI’s/Advisor’s/Boss’s job, then they are the right target for a mentor. If you want a different position, find another mentor. There are a ton of resource materials on nurturing a successful mentor relationship. Look to the societies you’re involved in, such as SFRBM, for help.

Rule #4: Make connections

An informational interview is all about getting to know someone and the place they work (and sharing a little bit about yourself too!). It’s not about flinging your CV at them (although you should have a copy ready to fling). There’s a nice entry about the Informational Interview here - http://thepostdocway.com/content/michelles-corner.

Rule #5: Know your Resources

There are a myriad of great web sources at our disposal to take advantage of.

Remember, your future is up to you. It is your responsibility to reach your own goals.

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Category: Education


Radical View – Christopher Kevil, Ph.D.

By: Sumitra Miriyala, Ph.D., LSU Health Sciences Center

SFRBM: Tell us about your background and when did you realize you were interested in science?

My initial realization of a love for science began in elementary school while performing a science fair project on different cellular functions of the brain. Soon after, I realized that I was fascinated with the idea of how tissues within organs work and how biochemical responses contribute to pathophysiology. This has guided my formal education and still contributes to my current research program.

SFRBM: Who has been your greatest teacher? What do you think the most important factors are that have shaped your career?

I have been lucky to have had input and advice from many outstanding teachers and mentors in the areas of free radical research, physiology and pathology over the years. However, I consider myself quite fortunate to have had two excellent free radical/redox biology leaders, Drs. Matthew Grisham and Victor Darley-Usmar, as outstanding teachers during my graduate and fellowship training. Their instruction helped me establish an important appreciation for free radical and redox biology research during disease that still impacts my research program today.

SFRBM: Briefly describe your research interest and what is the most notable research achievement from your lab?

My research interest centers on redox regulation of adaptive and pathophysiological vascular growth and remodeling. In my graduate work, I was keenly interested in how peroxides altered endothelial cell functions (e.g. solute barrier, growth, and inflammation properties). Over the years, it has become clear that several other redox molecules (e.g. GSH, NO, and H2S) also critically influence endothelial cell and vascular functions. From this collective interest, my research group has revealed that redox networks work together regulating numerous vascular functions. As for a notable research achievement, that’s a difficult question. It’s always challenging (if not impossible) to judge the impact of one’s own work. However, if pressed, I would say that our group has made significant strides in revealing the importance of GSH and NO metabolites for ischemic vascular remodeling along with identification of therapeutic strategies that have been tested in clinical trials. But, this area of investigation is still ‘young’ (so am I-I think!) and I believe more exciting discoveries are yet to come.

SFRBM: What do you think is the direction the Oxidative Stress field is heading?

I believe oxidative stress or redox biology is heading in several directions with disease and clinical based studies being an important area. However, as the Society is a leading ‘steward’ of the area, it is important that we collectively work to educate and enlighten the broader research community with a sense of collegiality and collaboration. I also believe future areas of oxidative stress will be in large network studies coupled with genomics, metabolomics and proteomics. I believe we are merely scratching the surface of the biochemical complexity of our field and have such little clear insight into how it cooperatively functions with other molecular systems.

SFRBM: In the current climate in which investigators are faced with decreased NIH funding for research and low morale, what is the best advice?

Collaboration, cleverness and persistence. In this current climate, we are all challenged to be the absolute best that we can be. Often times, this alone will not win the day. It is important to remember that collaboration with colleagues and experts beyond your area of expertise may provide new avenues and opportunities for funding. Persistence (a.k.a. ‘grit’) is also an overlooked attribute that is, of course, less glamorous but very important. Finally, I have also found that asking an important question regarding a poorly understood problem or topic is key in convincing a reviewer or study section that your project is meritorious and should be funded.

SFRBM: Being a mentor, you have shaped many students (graduate and postdoc) to enter academic and industry research, any tips how to shape individuals for these scientific fields?

I have found it important to help trainees identify what their true skills and strengths are so that they can begin to build a productive career from the beginning. I also encourage individuals to reflect on what it is they get enjoyment and pleasure from in science, as we all know that experiments fail and papers and grants may get rejected. Having a good sense of perspective and purpose are important over the course of one’s career.

SFRBM: The Center for Cardiovascular Diseases and Sciences at LSU Health Science Center Shreveport has recently been approved by the Louisiana Board of Regents and you now serve as the Director for this program can you explain the benefits this center can contribute to the scientific field?

Our new Center for Cardiovascular Diseases and Sciences (CCDS) provides several unique opportunities for redox biology research. Investigators at LSU Health Shreveport have had a long-standing history in oxidative stress and free radical research related to cardiovascular disease and inflammation. The newly established CCDS builds from this foundation and is extending into new areas of redox biology of cardiovascular disease including mitochondrial function, hydrogen sulfide metabolism, nitric oxide metabolism along with applications in disease models and translational clinical studies. We also have strong infrastructure supporting animal, molecular and redox biology studies coupled with a highly collaborative environment between numerous investigators.

SFRBM: How has science/research changed during your life as a scientist?

The state of scientific research has changed considerably over the years. What I have noticed the most difference in is the scale and magnitude of research. Today, big data initiatives (omics and others), accurate disease modeling and cross discipline collaboration are critically important areas for research success.

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

The annual SFRBM meeting is very important for myself and members of my laboratory. It provides numerous opportunities to network with old and new friends, learn the latest scientific developments and provide valuable educational opportunities through the pre-meeting workshop and Sunrise Free Radical school.

SFRBM: What are your hobbies outside the laboratory?

I enjoy traveling, hiking and fishing with my family and friends.

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Category: SfRBM Member Profile


Redox Theory of Aging

By: Dean P. Jones, Emory University

Click here to view the full article in the journal Redox Biology

Metazoan genomes encode exposure memory systems to enhance survival and reproductive potential by providing mechanisms for an individual to adjust during lifespan to environmental resources and challenges. These systems are inherently redox networks, arising during evolution of complex systems with O2 as a major determinant of bioenergetics, metabolic and structural organization, defense, and reproduction. The network structure decreases flexibility from conception onward due to differentiation and cumulative responses to environment (exposome). The redox theory of aging is that aging is a decline in plasticity of genome–exposome interaction that occurs as a consequence of execution of differentiation and exposure memory systems. This includes compromised mitochondrial and bioenergetic flexibility, impaired food utilization and metabolic homeostasis, decreased barrier and defense capabilities and loss of reproductive fidelity and fecundity. This theory accounts for hallmarks of aging, including failure to maintain oxidative or xenobiotic defenses, mitochondrial integrity, proteostasis, barrier structures, DNA repair, telomeres, immune function, metabolic regulation and regenerative capacity.

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Categories: Education, Redox Biology