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...
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...
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...
25Aug/16

“Interface of TH2 Inflammation and TGF-beta Signaling in Pulmonary Hypertension” – A Synopsis

Below is a synopsis of this video “Interface of TH2 Inflammation and TGF-beta Signaling in Pulmonary Hypertension”, a talk by Rubin Tuder given at the Vera Moulton Wall Center for Pulmonary Vascular Disease: Summary He has shown the first statistical correlation of perivascular inflammation with mPAP and vascular remodeling (~60 lungs from IPAH, hereditary PAH, scleroderma associated PH) despite current PH drugs: Schistosomiasis – 200 million people infected by parasite – in temperate areas like China, Brazil, Sudan, etc. 1-10% of people infected will develop PH Rather than talking about things where we don’t know what the cause/effect relationship is in PH (IPAH, Scleroderma, etc.), we should start with Schistosomiasis, which is something where we know what the culprit is: an egg nesting around vasculature that causes vasculopathy.… Read More...
04Aug/16

“Novel Insights Into Lung Autoimmunity Through Research In Rare Mendelian Diseases” – A Synopsis

This is a video by Dr. Anthony Shum from an excellent series of talks by the Vera Moulton Wall Center for Pulmonary Vascular Disease (a brief summary of which is below): Summary Exome sequencing (similar to what 23andMe does) can provide insight into rare Mendelian diseases. Specifically, Dr. Shum has used this to analyze patients with autoimmune interstitial lung disease patients (typically patients who present at a young age, have pulmonary hemorrhage, arthritis, and presence of the autoantibodies ANCA and ANA) and has found that they all contain a mutation in the COPA gene, which was predicted to be damaging. COPA is ubiquitously expressed, and enables protein transport between the Golgi Apparatus and the ER.… Read More...
01Aug/16

Regulation of Mitochondrial Metabolism and PH

The following is an excellent excerpt from Metabolic Regulation: A Human Perspective, by Keith N. Frayn. After reading it, the connection between metabolism (specifically mitochondrial oxidative metabolism capacity) and PH should be clear. I’ll leave the in depth commentary of why (including how, if this is true, PH is restricted to affecting lungs as opposed to systemic circulation) for another post: “An important aspect of metabolic regulation and its adaptation to different circumstances is the use of oxygen to oxidize nutrients and, hence, generate ATP. There are two aspects relevant to this chapter. The first is a series of mechanisms that increase the ability of tissues to conduct oxidative metabolism.… Read More...
31Jul/16

The Pentose Phosphate Path and PH, Part I – RBCs, G6PD, & GSH

The pentose phosphate pathway (PPP) is a metabolic pathway that parallels glycolysis. In cells, within the cytosol, glucose is converted into glucose 6-phosphate (catalyzed by the enzyme hexokinase), which can then either 1) enter glycolysis (and subsequent glucose oxidation via citric acid cycle) to produce ATP, or 2) enter the PPP. The PPP (diagram below) is primarily an anabolic pathway; the primary purpose being the following: to produce molecules (specifically 5 carbon sugars, and Ribose-5-phosphate) used for fatty acid synthesis, nucleic acid synthesis, and protein synthesis. However, another important purpose of the PPP is to produce NADPH, a high energy electron carrier.… Read More...