The Post-Synaptic Density of Human Postmortem Brain Tissues: An Experimental Study Paradigm for Neuropsychiatric Illnesses

Recent molecular genetics studies have suggested various trans-synaptic processes for pathophysiologic mechanisms of neuropsychiatric illnesses. Examination of pre- and post-synaptic scaffolds in the brains of patients would greatly aid further investigation, yet such an approach in human postmortem tissue has yet to be tested. We have examined three methods using density gradient based purification of synaptosomes followed by detergent extraction (Method 1) and the pH based differential extraction of synaptic membranes (Methods 2 and 3). All three methods separated fractions from human postmortem brains that were highly enriched in typical PSD proteins, almost to the exclusion of pre-synaptic proteins. We examined these fractions using electron microscopy (EM) and verified the integrity of the synaptic membrane and PSD fractions derived from human postmortem brain tissues. We analyzed protein composition of the PSD fractions using two dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS) and observed known PSD proteins by mass spectrometry. Immunoprecipitation and immunoblot studies revealed that expected protein-protein interactions and certain posttranscriptional modulations were maintained in PSD fractions. Our results demonstrate that PSD fractions can be isolated from human postmortem brain tissues with a reasonable degree of integrity. This approach may foster novel postmortem brain research paradigms in which the stoichiometry and protein composition of specific microdomains are examined

The pharmacology of selective inhibition of COX-2

Grosser T. The pharmacology of selective inhibition of COX-2. Thrombosis and Haemostasis. 2006;96(4):393-400

Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis

Grosser T. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. New England Journal of Medicine. 2017;376(14):1389-1390

microRNA represses macromolecule

Grosser T. microRNA represses macromolecule. Blood. 2015;125(22):3365-3366

The cardiovascular pharmacology of COX-2 inhibition

Fries S, Grosser T. The cardiovascular pharmacology of COX-2 inhibition. Hematology Am Soc Hematol Educ Program. 2005;2005(1):445-451.Selective inhibitors of cyclooxygenase (COX)-2, the coxibs, were developed to inhibit inflammatory prostaglandins derived from COX-2, while sparing gastroprotective prostaglandins primarily formed by COX-1. However, COX-2-derived prostaglandins mediate not only pain and inflammation but also affect vascular function, the regulation of hemostasis/ thrombosis, and blood pressure control. All coxibs depress COX-2-dependent prostacyclin (PGI2) biosynthesis without effective suppression of platelet COX-1-derived thromboxane (Tx) A2, unlike aspirin or traditional nonsteroidal anti-inflammatory drugs, which inhibit both COX-1 and COX-2. The actions of PGI2 oppose mediators, which stimulate platelets, elevate blood pressure, and accelerate atherogenesis, including TxA2. Indeed, structurally distinct inhibitors of COX-2 have increased the likelihood of hypertension, myocardial infarction and stroke in controlled clinical trials. The detection of these events in patients is related to the duration of exposure and to their baseline risk of cardiovascular disease. Thus, coxibs should be withheld from patients with preexisting cardiovascular risk factors, and exposed patients at low cardiovascular baseline risk should be monitored for changes in their risk factor profile, such as increases in arterial blood pressure

Mechanism of variability in the response to low dose Aspirin

Fries S, Grosser T. Mechanism of variability in the response to low dose Aspirin. Clinical Pharmacology & Therapeutics . 2022

Weight-adjusted aspirin for cardiovascular prevention

Theken KN, Grosser T. Weight-adjusted aspirin for cardiovascular prevention. The Lancet. 2018;392(10145):361-362

Bioactivation of nitroglycerin in vascular smooth muscle cells is different from that in non-vascular tissue

Braun M, Grosser T, Schrör K. Bioactivation of nitroglycerin in vascular smooth muscle cells is different from that in non-vascular tissue. European Journal of Pharmacology. 1995;276(3):239-245.The mechanism of biotransformation of nitroglycerin into the pharmacologically active radical nitric oxide (NO) or a related compound is still unclear. Different enzymes have been discussed to be involved in the bioactivation process. The effects of inhibition of glutathione-S-transferase and cytochrome P-450 enzymes were investigated on nitroglycerin-induced relaxation of bovine and porcine coronary arteries and on nitroglycerin-induced activation of guanylyl cyclase in cultivated porcine aortic smooth muscle cells. The glutathione-S-transferase inhibitor sulfobromophthalein had no effect on nitroglycerin-induced vascular relaxation, nor on nitroglycerin-induced elevation of cGMP levels in porcine coronary artery smooth muscle cells. The modulation of cytochrome P-450 activity by selective inhibitors as well as inducers did not alter the bioactivity of nitroglycerin in both systems. The data demonstrate that the isoenzymes of both enzyme families, which have been shown to be involved in the metabolism of nitroglycerin in different non-vascular tissues, do not play a role in bioactivation of nitroglycerin in the vascular system

Elective affinities – Bioinformatic analysis of proteomic mass spectrometry data

Li X, Pizarro A, Grosser T. Elective affinities – Bioinformatic analysis of proteomic mass spectrometry data. Archives of Physiology and Biochemistry. 2009;115(5):311-319.Shotgun proteomic strategies based on the identification of proteolytic peptides by tandem mass spectrometry and sequence database searches have emerged as useful approaches for qualitative and quantitative measurement of proteins in large scale studies. Coincidentally, the automated analysis of the resulting mass spectrometry data has become increasingly challenging. Important steps in the analysis include the statistical validation of peptide and protein identifications, the extraction of quantitative information, and the interpretation of identified peptide and protein lists. This review discusses current informatics methods and software available to analyze shotgun proteomics data

Desktop IVC, HD IVC, Telepresence enabled by Research and Education Networks: Implications for Teaching

Desktop videoconferencing, high definition classroom videoconferencing and telepresence enabled by research and education networks are changing how teaching and learning occurs on the college campus. Join us for this session that examines the affordances and limitations of each interactive video technology, how REN infrastructure supports the use of such technologies, and how faculty from MAGPI member institutions are utilizing these technologies to enhance student learning, their own teaching practices and how they conduct research