28Oct/16

Appearances Can Be Deceiving – The Problem With Genetic Knockout Mice Studies

Appearances Can Be Deceiving – The Problem With Genetic Knockout Mice Studies When scientists want to study the effect that a gene has on an organism, they perform what is called a “knockout” experiment. The knockout method is an experimental method, usually employed in mice, whereby the expression of a specific gene under study is blocked. The goal of this method is to learn about what effect the absence of the gene has on the animal. Due to the inevitable rise in the importance of genetic targeting in therapeutics, the knockout model has become a very important staple in studying the functions and endogenous expression patterns of single genes in vivo.… Read More...
26Oct/16

“A proteomic approach to altered innate and adaptive immunity in the pathogenesis of PAH” – A Synopsis

Below is a synopsis of “A proteomic approach to altered innate and adaptive immunity in the pathogenesis of PAH”, a talk by Marlene Rabinovitch (MD, Stanford) given at the Vera Moulton Wall Center for Pulmonary Vascular Disease (video below). It is one of my favorite talks so far in this series of lectures… Hypothesis: there is an abnormal immune response (both innate and adaptive) affecting pulmonary arteries that is common in all forms of PAH Altered adaptive immunity in PAH pathogenesis What if antigens produced in lung are the site for autoantibody formation and immune complex deposition directly in the lung and in the perivascular area?… Read More...
20Oct/16

“Matrix metalloproteinases and their inhibitors in pulmonary hypertension” – A Review

This past week, I delved into the arena of Matrix Metalloproteinases and their role in disease and Pulmonary Hypertension. One of the first papers that I read with regards to this is by S.S. Pullamsetti et al. entitled “Matrix metalloproteinases and their inhibitors in pulmonary hypertension”. My review and summary of this paper is below. Abbreviations: ECs = Endothelial Cells SMCs = Smooth Muscle Cells ECM = Extracellular Matrix PAH = Pulmonary Arterial Hypertension MMPs = Matrix Metalloproteinases TIMPs = Tissue Inhibitors of Matrix Metalloproteinases In PAH, complex remodeling is observed in the pulmonary vasculature that involves all components of the blood vessel.… Read More...
08Oct/16

Protein Of The Week: Αlpha2-Macroglobulin

Alpha2-macroglobulin is a large protein that is present in plasma. It is synthesized by liver cells and fibroblasts. It’s main functions are the inhibition of proteinases; for example it inhibits plasmin (thus inhibiting fibrinolysis) and thrombin (thus inhibiting coagulation). However, it technically has the ability to inhibit proteases from all catalytic classes, as well as the potential to have its inhibitory function removed (via reaction of it’s thiol ester group with any primary amine group). The main mechanism by which it inhibits proteases is by steric hindrance: when the alpha2-macroglobulin approaches a protease, the protease cleaves the vulnerable region on the alpha2-macroglobulin (called a “bait” region) thus causing the alpha2-macroglobulin to collapse onto the protease.… Read More...
22Sep/16

Lectins, Tissue Transglutaminase, & PH

As per this talk by Robb Wolf at UCSF (at ~1 hour in), non-Western Huntington’s disease carriers don’t seem to express the disease. Since Huntington’s Disease is a rare genetic neurodegenerative disease, this is intriguing and suggests that the expression of the disease may be epigenetic. As he points out a few minutes later, tissue transglutaminase has been implicated in Huntington’s Disease. What does this have to do with epigenetics and PH? Tissue transglutaminase is an enzyme that is responsible for modifying most of the body’s proteins. A key tenant of the “Paleo Diet” and similar metabolic/nutritional therapies is that consumption of dietary lectins found in grains and legumes play a role in the development of a variety of diseases by escaping into the bloodstream from the gut and triggering immune responses as well as interacting with the enzyme tissue transglutaminase.… Read More...
08Sep/16

Dr. Rhonda Patrick On Cell Metabolism, Cancer, And More…

I recently listened to this podcast between Robb Wolf, author of The Paleo Solution and one of my favorite nutrition researchers, and Dr. Rhonda Patrick, founder of Found My Fitness and yet another one of my favorite researchers. It was a great discussion about a wide variety of topics mostly revolving around cell metabolism. I’ve included a summary of the key points discussed below. Summary & Key Points: For healthy cellular function and healthy aging in general, you need metabolic flexibility Once a cell acquires so much damage to the genome, it becomes glycolytic The act of becoming glycolytic does not cause a cell to become cancerous – immune cells, fast twitch muscle fibers, and astrocytes are all glycolytic but not cancerous In cancer, the mitochondria are still working, they are just dysfunctional Cells are primed to die.… Read More...
06Sep/16

“Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung” – A Review

This is a review and summary of a recent paper entitled “Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung”. In this study, metabolomic profiling was used in an animal model of PH to try to identify biomarkers of early stage PH, in hopes of identifying a process to diagnose PH earlier. At the end of this post, I’ve included a chart summarizing all of the biomarkers found in the study. Some terms: MCT = Monocrotaline SMC = Smooth Muscle Cell EC = Endothelial Cell Summary & Key Findings In the MCT animal model, they observed metabolic changes in “multiple pathways associated with the development of PH, including activated glycolysis, increased markers of proliferation, disruptions in carnitine homeostasis, increased inflammatory and fibrosis biomarkers, and a reduction in glutathione biosynthesis.” While less pronounced, the metabolic data derived from this study compared favorably with prior work carried out in humans with PH: “In support of our data in the MCT-exposed rat, PH patient metabolomic data also observed a significant elevation of glucose and fructose 6-phosphate levels [7].… Read More...
31Aug/16

Why “Starving Cancer” May Not Be So Bogus Of An Idea After All

It is well known that cancer cells switch their metabolism from a normal utilization of glucose and fats (glucose and fatty acid oxidation) to an abnormal, less efficient but more rapid, utilization of glucose. This abnormal utilization is referred to as glycolysis. When oxygen is not available, this is the pathway that is triggered.1 Glycolysis in itself doesn’t cause cancer per se, but it is a necessary consequence (i.e. necessary for cancer to develop). For example, our immune cells, red blood cells, cells lining the gut, and fast twitch muscle fibers, are all glycolytic, and they aren’t cancerous. They are glycolytic in order to rapidly proliferate (immune cells in response to infection, or gut cells to continuously be an effective barrier in the stomach), or in order to provide rapid energy when oxygen isn’t available in an adequate amount of time (e.g.… Read More...
30Aug/16

“AMPK modulates Hippo pathway activity to regulate energy homeostasis” – A Review

I’m on a YAP kick lately! This is another paper about the Hippo pathway and YAP but in relation to glucose homeostasis and cellular energy stress. In summary, the Hippo pathway is a tumor suppressor pathway. Energy stress, defects in glucose metabolism, and glucose starvation, all activate this pathway and decrease oncogenic downstream components (specifically YAP). The implications? Metabolic regulation and glucose homeostasis are integral pieces in the puzzle that is “What causes cancer?” Summary & Key Points: The Hippo pathway is a signaling pathway that is involved in the control of tissue and organ size in the body. Loss of the Hippo path components leads to tumor formation, which suggests that the Hippo path is crucial for suppressing tumors.… Read More...
26Aug/16

“Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension” – A Review

This was a very interesting and exciting paper that I discovered today via Pulmonary Hypertension News: “Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension”. I’m a large proponent of the hypothesis that metabolic dysregulation and immune dysfunction are key drivers in the development of pulmonary hypertension. This paper adds weight to my case that the former is most likely a key element in PH pathogenesis. I’ve also always believed that due to the enigmatic nature of the disease, and presence of “cancer”, “autoimmune”, and “metabolic dysregulation” like features, solving PH can potentially solve problems like cancer and autoimmunity. A few examples from the paper as it pertains to cancer: “Here, the identification of glutaminolysis as a mechanoactivated process coregulated with aerobic glycolysis advances our understanding of the regulatory hierarchy seen in the metabolic reprogramming in PH.… Read More...