Exercise-Induced Asthma

Exercise-induced asthma is a condition in which one’s airway constricts in response to exercise, particularly in response to exercise in cold, dry air. Those with exercise-induced asthma suffer from wheezing, coughing, chest tightness, and shortness of breath. It turns out that most people with exercise-induced asthma also suffer from airway constriction in response to other triggers (allergies, infections, etc.). The exact mechanism by which exercise causes airway constriction has not been fully discovered, but many pieces of this puzzle have been put together. In our bodies, we have immune cells that participate in inflammatory processes (in this case: airway constriction) in response to certain triggers. It is theorized that during exercise, the airway cooling and drying upon inhalation of cold, dry air and subsequent rewarming is what causes inflammation in asthmatics. This results in the release of inflammatory molecules from immune cells that cause the muscle in the airway to contract.

There are a few different ways to diagnose this condition. An effective way of doing so is a physical challenge test in which the subject performs their workout of choice and subsequent measures of how much air they can force out of their lungs in one second dictate whether or not they are an exercise-induced asthmatic. This is useful because the pre-exercise measure of exhaled air from the lungs will dramatically decrease in a subject whose airway constricts in response to exercise. Other diagnostic tests in which chemicals are used to induce airway constriction are not as specific to exercise-induced asthma, but they do show clinicians how reactive their patient’s airway is. Inhaled corticosteroids are used as a long-term treatment to reduce inflammation of the airway. Asthma is a chronic condition that must be managed by the patient and his/her doctor but cannot yet be cured.

The Brain’s Sugary Demise

Neurodegenerative diseases such as Alzheimer’s not only destroys the quality of life of patients, but also of their friends and families. Managing the psychological and cognitive effects of the brain lesions associated with Alzheimer’s disease is a devastating endeavor. Finding a way to thwart the progress or completely eradicate from the brain such a disease would be an incredible feat. We BCM441 students recently discussed the prevalence of Alzheimer’s disease in diabetic patients that have elevated systemic levels of glucose. In this Nature article, though, entitled “Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer’s disease: metabolic basis for dementia”, the researchers focus on patients without type 2 diabetes or impaired glucose tolerance and find that there are localized, significantly altered levels of multiple metabolites in the brains of Alzheimer’s disease (AD) patients (Xu et al. 2016).

The authors of this paper recognize that many different factors contribute to the onset of AD, but they aim to center their study on the metabolic aspect of the disease. These researchers used mass spectrometry to look at metabolite levels in seven different regions of the brains of nine AD patients and nine controls (post-mortem). They also studied plasma-glucose and plasma-copper (will be explained) levels in ante-mortem human brains. Their findings were very interesting. In the nine AD patients, glucose, fructose, and sorbitol levels were significantly elevated. However, the brain tissue in these patients was deficient in copper. They found that these metabolite levels in the ante-mortem brain tissue, though, were unaltered. In the nine AD patients, there was variation in the glucose elevation in different brain regions, and furthermore, they found that there were much higher levels of glucose in brain tissue that was more severely damaged. Levels of sorbitol and fructose varied insignificantly among different brain regions. Copper levels in the AD brain seemed to be inversely proportional to the levels of glucose. Hence, in tissues with very high glucose levels, there would be corresponding low levels of copper (Xu et al. 2016).

The increased levels of glucose, fructose, and sorbitol and decreased levels of copper in the brain tissue of AD patients were very significant and led to some interesting speculation and ideas for further discussion. What is amazing about these results is that we know that diabetics are often victims of AD, and the obvious similarity between diabetics and the patients in this study are that they have elevated glucose levels. It just happens to be systemic in diabetics and due to insulin resistance. So, we can see that these elevated metabolite levels have something to do with disease mechanism. Now we can address what the authors were thinking about these results.

Their first thought dealt with the fact that there is known decreased activity of GLUT1 transporters in AD, which is consistent with the fact that GLUT1 is the main glucose transporter in the blood brain barrier. The problem with this idea is that there are elevated glucose levels in the cell. Thus, the authors concluded that the high intracellular glucose levels (causing an unnaturally steep gradient) likely downregulates the expression of GLUT1, lowering its activity (Xu et al. 2016). So, why are these glucose levels so high? Well, it is also true that in AD, glycolysis and the TCA cycle are impaired. The authors cite that pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and cytochrome c oxidase/complex IV (mitochondrial enzymes) are impaired in AD (Xu et al. 2016). If the enzymes that catabolize glucose are not working, we probably have elucidated the mystery of the elevated glucose levels. This also seems to explain the alternative route for glucose down the polyol pathway, hence the elevated fructose and sorbitol levels.

Now that we have established possible causes for glucose elevation, how does this relate to neurodegeneration? First, advanced glycation end products (AGEs) must be discussed. This phenomenon is very prevalent in diabetes because of increased glucose levels. High glucose (and fructose) results in the formation of AGEs because of the aldehyde (and ketone), which can be attacked by reactive functional groups on macromolecules in the cell (Gkogkolou and Böhm 2012). It is known that AD brains contain N-epsilon-carboxymethyllysine (CML) which is an advanced glycation end product that coordinates divalent copper (decrease in copper levels is indeed VERY relevant) (Xu et al. 2016). CML essentially steals the copper away from enzymes that need it like cytochrome oxidase (complex IV in the electron transport chain!) – super important for cellular fuel – and superoxide dismutase, which helps to fight against oxidative damage (crucial for cell health). Increased glucose concentrations “drive CML-modification of collagen, which inhibits cell-copper uptake by suppressing cell-membrane copper transport via copper transporter 1” (Xu et al. 2016). If cytochrome c oxidase is deficient in copper, fuel production in cells can be severely impaired and cell death can ensue. The authors believe the big copper ordeal is a good place for a therapeutic target in AD patients (Xu et al. 2016).

In summary, this high impact work shows the science community that patients with AD exhibit localized, elevated brain glucose levels and there are a few mechanisms by which this can lead to neurodegeneration and the debilitating AD symptoms that follow. Drug therapies that hit these spots addressed in this study must be seriously considered in order to help better the lives of those unfortunate enough to encounter such a wicked disease.


Figure 1. This picture shows the formation of CML which, as described by the study, has heavy implications in the pathogenesis of Alzheimer’s Disease. Interestingly enough, the formation of this advanced glycation end product (given high glucose concentrations) does proceed through a Schiff base intermediate. 




Gkogkolou, Paraskevi, and Markus Böhm. 2012. “Advanced Glycation End Products.” Dermato-Endocrinology 4 (3): 259–70. doi:10.4161/derm.22028.

Xu, Jingshu, Paul Begley, Stephanie J. Church, Stefano Patassini, Selina McHarg, Nina Kureishy, Katherine A. Hollywood, et al. 2016. “Elevation of Brain Glucose and Polyol-Pathway Intermediates with Accompanying Brain-Copper Deficiency in Patients with Alzheimer’s Disease: Metabolic Basis for Dementia.” Scientific Reports 6 (June): 27524. doi:10.1038/srep27524.


Exercise-Induced Asthma: Themes and Innovations

For my Capstone Assignment, I have chosen to study exercise-induced asthma. I have suffered from this condition for many years, and as someone who likes to go to the gym, I would say that the effects of this are more on quality of life than anything else. Physical activity and cold air leave people like me feeling breathless and coughing incessantly. I have chosen to organize my project using three different categories. The first is diagnosis, the second is disease mechanism and causes, and the last is treatment. I have chosen these categories because they are fairly obvious and simple for a condition like asthma.

In the diagnosis category, the majority of literature seems to focus on two different types of tests, direct and indirect, that are used to determine whether or not a patient suffers from exercise-induced bronchoconstriction. Direct tests use pharmacological substances to see whether or not airway contractions are induced. Indirect tests mimic conditions one would face during physical activity that would induce asthmatic symptoms. Results are obtained from these tests and physicians can prescribe medications according to the severity of the patient’s asthma.

In the causes of disease category, the majority of the literature suggests that mast cells, which are white blood cells, contain inflammatory substances that are released and cause contractions of the smooth muscle in an asthmatic’s airway. Also, flux of ions through calcium channels is often disturbed which has an effect on smooth muscle. High levels of adenosine, phospholipase activity, and mucins (proteins in gel layer of airway surface liquid) have implications for causes of bronchospasms in exercise-induced asthmatics. Disease mechanism is not actually completely clear in asthmatics and there are many, many palliative treatments for the condition.

To treat asthma, many physicians use drugs that prevent the release of inflammatory mediators from mast cells, such as histamine. This attenuates bronchospasms. Moving downstream a bit, sometimes antagonists of the receptors of these mediators are used to prevent the inflammatory result (including calcium antagonists for the reasons mentioned in disease causes). Corticosteroids are often used to treat the condition. Ultimately, asthma cannot be cured, but its symptoms can be managed in pharmacological and non-pharmacological ways.

This condition, as was just mentioned, is one to be monitored and managed. The field comes down to using the right tests to diagnose and assess the severity of the exercise-induced bronchoconstriction and prescribing the right medications to reduce the inflammation of the airway that leaves a runner wheezing, coughing, and out of breath.

The Barres Family Blessings

Breast cancer as it relates to the BRCA2 genetic mutation:

The BRCA2 gene mutation runs in my family on my father’s side. My dad passed it down to me, and I have to see a genetic counselor and many doctors each year for cancer screening. My uncle Ben, who has the mutation, has suffered from three different kinds of cancer. He beat breast cancer when he was 40, thyroid cancer at 60, and now has advanced pancreatic cancer. I would like to know more about this mutation and the mechanism by which it increases my chances of getting cancer.


I have suffered from asthma my whole life. It is often an impediment to certain activities (running in the cold, painting my nails (weird trigger), etc.) and has been passed down to me from my father (thanks again, dad). It would be great to know more about a condition that so much of my family suffers from.


My grandfather had Parkinson’s disease. My uncle Ben, mentioned above, is actually a neuroscientist and is currently involved in drug trials with a drug he developed in his lab at Stanford that is supposed to thwart the progress of all neurodegenerative diseases, like Parkinson’s. It would be nice to be able to have a real conversation with Ben about his drug’s mechanism.

Identifying the Culprit: Who Started It?

It is so commonly observed that every individual knows at least one person with cancer. Since every cancer is unique, the treatments must be tailored to each cancer patient, hence, maintaining awareness of new, groundbreaking cancer therapies is so critical for clinicians and researchers. In the Nature article entitled “Targeting metastasis – initiating cells through the fatty acid receptor CD36”, the authors discover a potential interesting therapy for multiple forms of cancer.

The authors observe that a major blockade for progression in cancer research is that scientists have yet to identify the cells that are responsible for the initiation of metastasis, the spread of cancer cells to other parts of the body from the primary tumor. To study this issue, the authors injected a fluorescent lipophilic (“fat-liking”) dye into human oral carcinoma cells which were subsequently injected into the mouths of mice. It is critical to note that the researchers studied a population of cells that contain the CD44 gene, which, when expressed, often plays a role in tumor metastasis. More specifically, a subset of these cells express the CD36 gene, and this protein, which is a fatty acid receptor, plays a major role in metastasis via lipid metabolism according to this study. The authors wanted to isolate the label-retaining cells from the carcinoma, defined by their slow-cycling nature, as these cells have the potential to transition to mesenchymal cells which are stem cells in connective tissue. These cells were of interest because they play a role in cancer development. To the authors’ surprise, these slowly proliferating cells were indeed those that were expressing CD36 and CD44. Fatty acid metabolism genes were also being expressed in these cells, and this is what leads to some interesting findings.

Working our way through the details of metastasis initiation, the first finding was that CD36 does increases metastatic potential of cancer cells. The authors describe that the overexpression of CD36 not only leads to large increases in metastatic potential but also increases in size of the metastatic tumors. CD36 doesn’t seem to have an effect on the size of primary tumors, but it is certainly directly correlated with the size of tumors that resulted from the migration of cells from the original cancer site.

This begs the question: what is the mechanism by which CD36+ cells cause large increases in metastasis? It turns out that dietary lipids are deeply involved in this process. The label-retaining cells express genes that code for enzymes required for fatty acid oxidation. The largest metastases were found in mice that were fed diets with high fat content. The authors suspect that the expression of CD36 is related to the concentration of fatty acids, specifically palmitic acid. They note that the only observed effects were on metastasis levels and metastases sizes – not primary tumor growth. They further solidify this idea by pointing out that their data show that while CD36+ cells result in a high level of metastasis, CD36+ and CD36 cells yield primary tumors of the same size.

This research has some very obvious clinical implications related to thwarting metastasis of malignant tumor cells. Thus, the authors used antibodies that inhibit all discovered functions of CD36 and inoculated the mice. The mice received an injection every three days and the result was the prevention of metastasis initiation. Daily injections resulted in 80-90% size reduction of lymph node metastases. The ultimate idea is that targeting cells that are CD36+ and inhibiting its known functions may be a very effective therapy and prophylactic treatment of the spread of cancer. Such high impact results can have a major influence on new medicines and treatments of such a widespread disease. Clearly this work also relates to our recent discussions about lipids, and it is useful for us to see the impacts lipid metabolism has in areas we might not expect, like metastasis. Since – as already pointed out – most, if not all, of us know someone with cancer, it is possible for us to see this work materialize into treatments that effectively crash the spread of such a deadly disease first hand.


Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41-45 (2017).

This picture shows the high impact results of the paper. On the left, it is shown that the CD36 antibody has no significant effect on the primary tumor growth. On the right, however, the size of the metastases is reduced due to treatment with the antibody.

Significant finding on fatty acid oxidation role in endothelial cells

A recent study has revealed a surprising, significant finding on the role of fatty acid oxidation in endothelial cells. Endothelial cells are required for angiogenesis, or the formation of blood vessels. This process has many clinical implications for diseases like cancer and particularly for developmental issues during early life stages in which growth is very extensive. The paper begins with a description of the role of fatty acid oxidation in blood vessel formation. Proliferation and migration of endothelial cells are necessary for blood vessel growth, and the study notes that fatty acid oxidation’s major effect is on proliferation. Without cell proliferation, blood vessels clearly cannot form which can be a preventative process for certain diseases or have a detrimental defect. The greatest area of focus in this study is on carnitine palmitoyltransferase 1 (CPT1) which is an enzyme involved in the rate limiting step of fatty acid oxidation. Human endothelial cells are rich in the isoform CPT1A, so the researchers silenced this enzyme in these cells and studied the effects.

The result of this silencing was that endothelial cells were not proliferating as they typically would. Proliferation decreased in knockdown cells in which fatty acid oxidation was being thwarted. The researchers then considered multiple feasible options as to why endothelial cell proliferation increased in these CPT1Akd cells. From an energetics standpoint, it was discovered that proliferation was not impacted by a lack of ATP in the cells as a result of the enzyme silencing. The knockdowns also did not have a high level of toxicity from reactive oxygen species due to the lack of fatty acid oxidation. What follows these results is a high impact discovery.

The carbons from fatty acid oxidation in endothelial cells are largely used for the synthesis of deoxynucleoside triphosphates. These dNTPs are then used for DNA synthesis and cell proliferation. Thus, if the concentration of dNTPs inside the cell suffers from a large decrease, cell proliferation will obviously also be affected. In most cells, as the authors point out, carbons from glucose and glutamine are what feed into the citric acid cycle. Intermediates from this cycle often end up being incorporated into DNA, so it is surprising that these endothelial cells so highly depend on fatty acid oxidation as a carbon source as opposed to what most other cells use. The authors describe that this can have major clinical implications for a way of inhibiting pathological angiogenesis. Even for inexperienced readers, this paper does demonstrate the high significance of the findings.


Schoors, S. et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520, 192-197 (2015).


Why Biochemistry…

The first thing I was told about biochemistry was that the most basic description of this area of study was: the chemistry inside of a cell. That stuck with me because anytime someone asks me to describe biochemistry, this is what I come up with. Sometimes I throw in that a biochemistry course largely focused on the chemistry side would basically entail learning relevant organic chemistry. After taking BIO220, I came away with a couple basic themes and objectives when it comes to studying the chemistry inside of a cell. 1) Evolution has yielded some really interesting processes that seem backwards and inefficient but work, and 2) the value of understanding biological chemistry lies in a student’s newfound ability to predict what will happen in a system that they have not yet been exposed to. We biochem students don’t want to just know things. We want to solve problems, think, and stretch our intellect and that is what draws me to the major.

I am majoring in math as well, and I do find that my greatest fixation tends to be on mathematics. I am able to avoid wet labs and solve interesting problems. I get the opportunity to think abstractly about sets of elements and prove theorems. I have discovered so much about the world and myself through these processes and I often find myself encountering the same phenomena in biochemistry. In both areas, I must be patient with myself and my ability to understand something I will never be able to see or touch.

I do believe that my future career will not revolve around the sciences. I don’t think I could ever bear to leave theoretical mathematics, however, studying biochemistry has armed me with intellectual skills that will help me in any field. I have learned how to learn and how to think metacognitively. Challenging material makes students more sophisticated, mature learners and more accustomed to rising up to a level that sometimes feels out of reach.