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October 2013 Archive

Posted by Chris on October 3rd, 2013  ⟩  0 comments

Necrosis is a very bad thing. I used to think that all cell death was bad, but that was before I began to understand the difference between apoptosis and necrosis. In its most basic form: Apoptosis = good cell death and Necrosis = bad cell death. That may be a little too simple, but it was the beginning of my understanding of some of the intricacies of cellular response to damage, disease or stress.

There has been a lot of research over the last 10 years focusing on cell stress and cell death and the molecular pathway differences between the two types of cell death. In apoptosis, the programmed death of a cell, cells naturally expire and produce apoptotic bodies which can be properly engulfed by phagocytes and removed before they can cause damage. The process of apoptosis is critical in embryonic development for processes like separating our fingers into individual digits and the overexpression or underexpression of apoptosis can cause problems like atrophy or cancer.

Necrosis, on the other hand, is the completely unplanned death of a cell, or at least unplanned by the cell. There are lots of causes for necrosis; including physical injury, infection, or toxicity. Cells that undergo necrosis do not elicit the proper signal pathways for the phagocytes. Instead, they uncontrollably release their contents into the intracellular space, causing inflammation or spreading the cause for the necrosis into surrounding cells. The result is a cascading effect of cell death that results in things like gangrene.

As scientists have begun to understand this process, one of the things they discovered was a wide array of damage associated molecular pattern molecules, or more easily called DAMPs. DAMP molecules are commonly released in the process of necrosis, but are prevented from release during apoptosis. IL1A is one such DAMP molecule that is responsible for activating an immunity response. The immunity response from DAMPs causes sterile inflammatory response which has been shown to be a factor in many diseases including atherosclerosis, ischemia reperfusion injury and Alzheimer's. Increased IL1 activity has also been associated with diabetes, rheumatoid arthritis, gout, and psoriasis.

IL1R1Since IL1A is universally expressed, it is believed to act as a universal DAMP molecule, but the actual process has still be unclear. While it was known that the pro-IL1A (p33) is processed to the mature IL1A (p17) by calpain, it was not known what the consequences were for that cleavage. Yue Zheng et al. describe in a recent paper that the cleavage of p33 is essential for IL1A and increases its affinity for IL1R1 (Receptor 1). What they found was that IL1A is primarily bound by IL1R2 (Receptor 2), which protects it from cleavage and prevents its activity. In fact, without IL1R2, the most significant DAMP in necrotic cells is IL1A. They showed that IL1R1 rich tissue (e.g. liver) activated the immune response regardless of IL1A cleavage, whereas IL1R1 deficient tissue (e.g. kidney) that cannot cleave p33 did not respond to IL1A at all.

There are other DAMP molecules, of course, and IL1A isn’t the only molecule that can drive inflammation, but Zheng points out that the additional activation of IL1A might just act as the tipping point of the inflammatory response that drives it toward adaptive immunity. Zheng has found that IL1R2 controls the release of Il1A through the activation of caspase-1, which processes IL1R2 and releases IL1A for binding to IL1R1 and cleavage by calpain.

Fundementally, this paper presents a small, but meaningful step toward understanding the roles of these molecules play in situations like graft rejection or chronic diseases like Alzheimer's and atherosclerosis. And ultimately, we can hope that this knowledge will help doctors work around these types of problems in the future.

 
 

Zheng, Y., Humphry, M., Maguire, J. J., Bennett, M. R., & Clarke, M. C. (2013). Intracellular Interleukin-1 Receptor 2 Binding Prevents Cleavage and Activity of Interleukin-1α, Controlling Necrosis-Induced Sterile Inflammation. Immunity. 38, 285–295

Category Code: 88221 79101

Posted by Chris on October 10th, 2013  ⟩  0 comments

What if cases of delirium or instances of delusions were only a symptom of an imbalance of inflammatory growth factors in your brain? What if the root cause for debilitating mental diseases, such as Alzheimer’s, were really grounded in the never-ending tug and pull balancing act between cytokines and chemokines, their receptors and their inhibitors that goes on inside each of us every day? What if the whole of “getting older” (the joint pain, the memory lapses, etc.) was just a side effect of the messed up secretions of interleukins, fibroblast growth factors (FGFs), and other growth factors that we unknowingly depend on without even knowing what for? Those are some of the questions which motivated Dunja Westhoff and colleagues from the University of Amsterdam to try to find out.

esthoff and her group decided to look into the pre-operative expression pattern of cytokines in elderly patients who were admitted for hip fracture. A large percentage of elderly patients with hip fractures suffer from post-operative delirium, which seems to make sense since both the fracture and the surgery lead to systemic responses. Of course, discovering the subtleties of cytokine expression in elderly patients is no walk in the park. They were unable to detect 5 cytokines at all and 21 other cytokines were only detectable in a minority of the patients…leaving just 22 growth factors (including FGF2, IL1B, IL2, IL3, IL4, IL6, TNF-α, and EGF) that could be measured across both patients suffering from delirium and those who did not.

They eventually focused on 4 cytokines, three that had significantly lower levels (Flt-3L, IL1RA, and IL6) and one that was significantly higher (IP-10) in post-operative delirious patients. IL1RA (also listed as IL1RN) is a natural inhibitor of IL1A and IL1B, which are both pro-inflammatory cytokines in the brain. Subsequently, the reduction of IL1RA would lead to higher inflammation in the brain. Decreased levels of IL1RA have also been previously observed in patients suffering from either Alzheimer’s or rheumatoid arthritis.

This is a small study, and knowingly limited in its findings. But there seems to be a spark of truth amongst the clutter of results. Westhoff’s results seem to agree that there is a neuroinflammatory response effect which may be at least partially responsible for cases of delirium. Consequently, this may become an exciting avenue of clinical study and research. More research is necessary in order to prove if the effect is due to heightened proinflammatory responses or reduced anti-inflammatory responses. As usual, we have so much yet to learn. But, if true, this should lead to some exciting breakthroughs!

 
 

Westhoff, D., et al. (2013). "Preoperative cerebrospinal fluid cytokine levels and the risk of postoperative delirium in elderly hip fracture patients." J Neuroinflammation 10(1): 122.

Category Code: 79101

Posted by Chris on October 17th, 2013  ⟩  0 comments

The field of regenerative limb research is nowhere near as populated as some of the other biological sciences, like cancer research or stem cell research, but there is a fundamental importance to learning all we can from the creatures who possess this wonderful trait. Ed Yong wrote an awesome review of the subject some time ago on his blog “Not Exactly Rocket Science” which is definitely worth the read in order to gain some perspective on the entire field of regenerative research (and also definitely worth bookmarking in order to read some of the best reviews I have found on popular science).

One of the quotes from Ed’s article that really struck me at the time was, “[Ashley] Seifert doubts we will ever have an injectable cocktail of molecules that triggers regeneration.” I had a good chuckle then and again when I reread it this morning because that seemed exactly like the kind of quote that motivates a determined and tenacious scientist to overcome the odds and discover something miraculous. Of course, no one said science is easy, but this month a small group out of India may have discovered the first key ingredient for a regenerative cocktail.

Suresh Balakrishnan’s group worked with a common gecko called Hemidactylus flaviviridis, or the Yellow-bellied House Gecko. Like other geckos, it is readily able to discard its tail and grow a complete new tail, given enough time. (If you’d like to read an article about the intriguing mechanism of a gecko losing its tail in the first place, go to LiveScience.) Balakrishnan assumed that there must be several growth factors and receptors involved in the process of limb bud development, and it is also well known that FGF2 plays a critical role in epimorphosis from previous studies on salamanders and chick embryos. In order to further our understanding of vertebrate systems, they looked at gecko tail regeneration both in the presence or absence of an FGFR inhibitor, SU5402, a known tyrosine kinase inhibitor that would disrupt the FGF2-FGFR1 signaling pathway.

Gecko Tail RegenerationThey tested 3 different stages of development with the inhibitor and found that FGF2 was quite important for early limb bud development. In fact, there was an inhibition of the formation of the wound epithelium as well as an inhibition of the formation of the blastema. But at later stages, once the blastema had already developed, there was little to no effect of the FGFR inhibitor on continued growth. Histological profiling of the tissue additionally showed retardation of mesenchymal cell differentiation, ependymal growth and blood vessel formation, all things known to be developmentally moderated by FGF2.

Of course, this isn’t the whole story. While Balakrishnan’s group saw a slowdown in bud formation and tail growth, it did still grow, if only at half the rate of a normal gecko. So there are likely multiple pathways that the cells can utilize to gain the same end goal, albeit not always equally. There is also the “small” question of which growth factors or chemicals contribute to the continued elongation of the cells after the point of limb bud formation when FGF2 stops being the big dog in the playground.

The interesting part of this kind of research to me isn’t the direct results on limb regeneration or whether humans may ever achieve that (I think we’re closer to using stem cell scaffolds and biological 3-D printers to get the same result!), but the other avenues that this research can lead, such as nerve regeneration for paraplegics or quadriplegics or perhaps even neural regeneration for stroke victims. The knowledge of how cells propagate and proliferate into organs is still a very mysterious process, but research such as this are slowly illuminating the pathway and dispelling the shadows of our understanding. One day soon, we will have that regenerative cocktail.

 
 

Pillai, A., Desai, I., & Balakrishnan, S. (2013). Pharmacological inhibition of fgfr1 signaling attenuates the progression of tail regeneration in the northern house gecko Hemidactylus flaviviridis. International Journal of LifeSciences Biotechnology & Pharma Research (2); Issue 4, pp. 263-278.

Category Code: 79101

Posted by Chris on October 24th, 2013  ⟩  0 comments

Obesity is one of best covered, and at the same time worst covered, topic in the news. Rightly so, since nearly every person is somehow or another hyper-concerned about their weight. Do I weigh too much? Do I not weigh enough? Does my weight accurately reflect my health? What is considered a “good” weight for my size/ build/ age/ comfort/ activity level? The news stories often hurt those efforts as much as they help. Reporters are quick to jump to the next, newest research to deplore our current state (whatever state that is). They are quick to instigate us to into trying the newest weight treatment plan. Other times they leap out in order to tell us why the previous newest weight treatment plan isn’t working for us or is possibly even harmful for us. And if all of that isn’t bad enough, worrying about it and stressing about it also causes weight gain! What a circle!

The good coverage focuses on our health. There is a strong correlation between being overweight and having Type 2 diabetes, for instance. Now, that doesn’t mean that every person who is overweight has or will get diabetes. But it’s just like when a baseball pitcher throwing strikes. There’s no guarantee that every pitch will be hit for a home run, but there sure is a better chance of it if the ball is constantly over the plate! And even though we live in an age where Type 2 diabetes is treatable, we still do not know the exact reason in which some biological systems becomes diabetic whereas others do not. To further our understanding of insulin resistance, the NIH has funded over $1 billion dollars each over the last three years. Those dollars are yielding fascinating clues.

Over the last decade, some key players have begun to emerge in insulin resistance. Cytokines and growth factors, ever-present in every system of our bodies whether we know it or not, work in conjunction with insulin to regulate blood sugar and fat deposits. One critical growth factor that has generated a lot of news recently is Fibroblast Growth Factor 21 (FGF21). FGF21 is an endrocrine protein (hFGF) of the FGF family of growth factors. The hFGF family typically has low affinity for heparin-binding sites and has been found to act on target cells far from their site of production. These FGFs play a significant role as regulatory hormones in bile acid metabolism, phosphate and Vitamin D metabolism as well as postnatal energy metabolism. The hFGF family also requires the use of co-receptors, like Klotho or βKlotho in order to activate any FGFRs, indicating that they have evolved a novel mechanism of regulation unlike any of the other FGF genes.

FGF21 in LiverFGF21 is primarily secreted by the liver and has been shown to play a role as an antidiabetic and antiobesity agent, activating thermogenesis in brown adipose tissue and increasing body temperature. But though FGF21 is considered to be metabolically protective, helping the body to resist obesity, fatty liver and insulin resistance, it is also found in higher levels in obese conditions and does not change with weight loss (though significant fasting leads to an increase in FGF21 levels). Recently, a group led by Dorit Somocha-Bonet, from the University of New South Wales, looked into the effect of overfeeding on several growth factors, including FGF21 and FABP4. Somocha-Bonet’s group found correlations with previous work that FGF21 increase is directly related to the increased delivery of fatty acids to the liver and also discovered that FGF21 is regulated by both feeding AND fasting signals, probably in an attempt to maintain insulin sensitivity. However, their FABP4 results contrasted with previous studies which showed that weight loss and exercise also reduced FABP4. Instead, they showed that FABP4 is not increased with overfeeding, suggesting that FABP4 production is a consequence of something later in an obese state.

There is still a lot of work that needs to be done to best understand these interactions. But piece by piece, I believe that we will crack the biological code around diabetes and learn to treat the cause instead of just the symptoms…and maybe one day throw that obese batter a curve ball.

 
 

Heilbronn LK, Campbell LV, Xu A, Samocha-Bonet D (2013) Metabolically Protective Cytokines Adiponectin and Fibroblast Growth Factor-21 Are Increased by Acute Overfeeding in Healthy Humans. PLoS ONE 8(10): e78864. doi:10.1371/journal.pone.0078864

Category Code: 79102 88221 79101