Browsing by Subject "Fibrillation"

Now showing 1 - 3 of 3
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    Effects of Various Flavonoids on the -Synuclein Fibrillation Process
    (Hindawi, 2010-01-28) Meng, Xiaoyun; Munishkina, Larissa A.; Fink, Anthony L.; Uversky, Vladimir N.
    α-Synuclein aggregation and fibrillation are closely associated with the formation of Lewy bodies in neurons and are implicated in the causative pathogenesis of Parkinson's disease and other synucleinopathies. Currently, there is no approved therapeutic agent directed toward preventing the protein aggregation, which has been recently shown to have a key role in the cytotoxic nature of amyloidogenic proteins. Flavonoids, known as plant pigments, belong to a broad family of polyphenolic compounds. Over 4,000 flavonoids have been identified from various plants and foodstuffs derived from plants and have been demonstrated as potential neuroprotective agents. In this study 48 flavonoids belonging to several classes with structures differing in the position of double bonds and ring substituents were tested for their ability to inhibit the fibrillation of α-synuclein in vitro. A variety of flavonoids inhibited α-synuclein fibrillation, and most of the strong inhibitory flavonoids were also found to disaggregate preformed fibrils.
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    Perspective: a dynamics-based classification of ventricular arrhythmias
    (Elsevier, 2015-05) Weiss, James N.; Garfinkel, Alan; Karagueuzian, Hrayr S.; Nguyen, Thao P.; Olcese, Riccardo; Chen, Peng-Sheng; Qu, Zhilin; Department of Medicine, IU School of Medicine
    Despite key advances in the clinical management of life-threatening ventricular arrhythmias, culminating with the development of implantable cardioverter-defibrillators and catheter ablation techniques, pharmacologic/biologic therapeutics have lagged behind. The fundamental issue is that biological targets are molecular factors. Diseases, however, represent emergent properties at the scale of the organism that result from dynamic interactions between multiple constantly changing molecular factors. For a pharmacologic/biologic therapy to be effective, it must target the dynamic processes that underlie the disease. Here we propose a classification of ventricular arrhythmias that is based on our current understanding of the dynamics occurring at the subcellular, cellular, tissue and organism scales, which cause arrhythmias by simultaneously generating arrhythmia triggers and exacerbating tissue vulnerability. The goal is to create a framework that systematically links these key dynamic factors together with fixed factors (structural and electrophysiological heterogeneity) synergistically promoting electrical dispersion and increased arrhythmia risk to molecular factors that can serve as biological targets. We classify ventricular arrhythmias into three primary dynamic categories related generally to unstable Ca cycling, reduced repolarization, and excess repolarization, respectively. The clinical syndromes, arrhythmia mechanisms, dynamic factors and what is known about their molecular counterparts are discussed. Based on this framework, we propose a computational-experimental strategy for exploring the links between molecular factors, fixed factors and dynamic factors that underlie life-threatening ventricular arrhythmias. The ultimate objective is to facilitate drug development by creating an in silico platform to evaluate and predict comprehensively how molecular interventions affect not only a single targeted arrhythmia, but all primary arrhythmia dynamics categories as well as normal cardiac excitation-contraction coupling.
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    Towards Better Diabetes Therapeutics: Designing a More Stable Insulin Analog
    (2023-03) Sambou Oumarou, Oumoul Ghaniyya Faiza; Weiss, Michael; Georgiadis, Millie M.; Hoang, Quyen Q.; Sims, Emily
    Insulin is a hormone that plays a central role in the regulation of human metabolism, and as a drug, is used in the treatment of diabetes mellitus. Hyperglycemia characterizes this condition due to a range of reasons from impaired insulin production by pancreatic beta cells to abnormalities resulting in resistance to insulin action. Depending on time and mechanism of action, the main types of insulin analogs are basal and prandial. Basal insulin analogs are slow-acting insulins that maintain a continuous basal level of insulin in the bloodstream. Prandial insulin analogs are fast-acting and their therapeutic goal is to avoid immediate and late post-prandial hyperglycemia. Most analogs face the problem of chemical degradation and amyloid-like fibril formation (fibrillation) in delivery devices. Thus, many modifications have been made to insulin in the effort to make it more stable and faster-acting. This thesis aims to study the effects of modifications that could be used to design an insulin analog with improved chemical and physical properties, while maintaining biological activity. We studied six amino-acid substitutions to native human insulin in different combinations: desB1 , AB2 , EB3, EA8 , EA14, and EB29. Analogs of the protein were chemically synthesized. Then, fibrillation and circular dichroism assays were performed using purified proteins. The results suggested that EB3 and EA14 are stabilizing modifications that prevent fibril formation, whereas EA8 and EA14 increase the structural stability of an analog. Our findings also suggested that certain modifications in isolation may not impact overall stability, but when combined with others, may show detectable effects, which is why EA8 and EA14 became the focus of further experiments. Cell-based activity assays indicated that all the analogs had similar biological activities. Future work will assess chemical degradation, solubility, amide proton exchange (as monitored by NMR), and mitogenicity.