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1
Pytowski, Lior, Chiu Fan Lee, Alex C. Foley, David J. Vaux, and Létitia Jean. "Liquid–liquid phase separation of type II diabetes-associated IAPP initiates hydrogelation and aggregation." Proceedings of the National Academy of Sciences 117, no. 22 (May 15, 2020): 12050–61. http://dx.doi.org/10.1073/pnas.1916716117.
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Amyloidoses (misfolded polypeptide accumulation) are among the most debilitating diseases our aging societies face. Amyloidogenesis can be catalyzed by hydrophobic–hydrophilic interfaces (e.g., air–water interface in vitro [AWI]). We recently demonstrated hydrogelation of the amyloidogenic type II diabetes-associated islet amyloid polypeptide (IAPP), a hydrophobic–hydrophilic interface-dependent process with complex kinetics. We demonstrate that human IAPP undergoes AWI-catalyzed liquid–liquid phase separation (LLPS), which initiates hydrogelation and aggregation. Insulin modulates these processes but does not prevent them. Using nonamyloidogenic rat IAPP, we show that, whereas LLPS does not require the amyloidogenic sequence, hydrogelation and aggregation do. Interestingly, both insulin and rat sequence delayed IAPP LLPS, which may reflect physiology. By developing an experimental setup and analysis tools, we show that, within the whole system (beyond the droplet stage), macroscopic interconnected aggregate clusters form, grow, fuse, and evolve via internal rearrangement, leading to overall hydrogelation. As the AWI-adsorbed gelled layer matures, its microviscosity increases. LLPS-driven aggregation may be a common amyloid feature and integral to pathology.
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Gudkova, Alexandra Ya, Olga I. Antimonova, and Mikhail M. Shavlovsky. "Role of pancreatic amyloidosis in pathogenesis of type 2 diabetes mellitus." Medical academic journal 19, no. 2 (September 18, 2019): 27–36. http://dx.doi.org/10.17816/maj19227-36.
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The occurrence of type 2 diabetes mellitus (T2DM) in developed countries is currently becoming epidemic primarily due to the changes in quality of life. This disease typically makes progress for a long time, and its clinical pattern is mostly related to various micro- and macrovascular complications. In addition to said complications the pancreas itself often undergoes damage associated with amyloid formation in islets of Langerhans which results in a toxic effect on the hormone-producing islet cells. Ultimately, hormone overproduction in T2DM shifts to hormone deficiency. The crucial causative factor of the development of pancreatic amyloidosis in T2DM is а short peptide hormone, amylin (IAPP), which is cosecreted with insulin and considered to be a kind of insulin antagonist. The present review reports structure, functions and amyloidogenic properties of human IAPP. The basic concepts of molecular and cellular aspects concerning pathogenesis of pancreatic amyloidosis have been provided. Patterns of the development of pancreatic amyloid lesions and possible approaches for early diagnosis and treatment of this significant complication of T2DM have been discussed.
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Roesti, Elisa S., Christina N. Boyle, Daniel T. Zeman, Marcos Sande-Melon, Federico Storni, Gustavo Cabral-Miranda, Alexander Knuth, Thomas A. Lutz, Monique Vogel, and Martin F. Bachmann. "Vaccination Against Amyloidogenic Aggregates in Pancreatic Islets Prevents Development of Type 2 Diabetes Mellitus." Vaccines 8, no. 1 (March 2, 2020): 116. http://dx.doi.org/10.3390/vaccines8010116.
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Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by insulin resistance and insufficient insulin secretion to maintain normoglycemia. The majority of T2DM patients bear amyloid deposits mainly composed of islet amyloid polypeptide (IAPP) in their pancreatic islets. These—originally β-cell secretory products—extracellular aggregates are cytotoxic for insulin-producing β-cells and are associated with β-cell loss and inflammation in T2DM advanced stages. Due to the absence of T2DM preventive medicaments and the presence of only symptomatic drugs acting towards increasing hormone secretion and action, we aimed at establishing a novel disease-modifying therapy targeting the cytotoxic IAPP deposits in order to prevent the development of T2DM. We generated a vaccine based on virus-like particles (VLPs), devoid of genomic material, coupled to IAPP peptides inducing specific antibodies against aggregated, but not monomeric IAPP. Using a mouse model of islet amyloidosis, we demonstrate in vivo that our vaccine induced a potent antibody response against aggregated, but not soluble IAPP, strikingly preventing IAPP depositions, delaying onset of hyperglycemia and the induction of the associated pro-inflammatory cytokine Interleukin 1β (IL-1β). We offer the first cost-effective and safe disease-modifying approach targeting islet dysfunction in T2DM, preventing pathogenic aggregates without disturbing physiological IAPP function.
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Akter, Rehana, Ping Cao, Harris Noor, Zachary Ridgway, Ling-Hsien Tu, Hui Wang, Amy G. Wong, et al. "Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology." Journal of Diabetes Research 2016 (2016): 1–18. http://dx.doi.org/10.1155/2016/2798269.
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The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes toβ-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formationin vivoorin vitroare not understood and the mechanisms of IAPP inducedβ-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms ofβ-cell death, the relevance of reductionist biophysical studies to the situationin vivo, the molecular mechanism of amyloid formationin vitroandin vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy.
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Westermark, Gunilla T., and Per Westermark. "Transthyretin and Amyloid in the Islets of Langerhans in Type-2 Diabetes." Experimental Diabetes Research 2008 (2008): 1–7. http://dx.doi.org/10.1155/2008/429274.
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Transthyretin (TTR) is a major amyloid fibril protein in certain systemic forms of amyloidosis. It is a plasma protein, mainly synthesized by the liver but expression occurs also at certain minor locations, including the endocrine cells in the islets of Langerhans. With the use of immunohistochemistry and in situ hybridization, we have studied the distribution of transthyretin-containing cells in islets of Langerhans in type-2 diabetic and nondiabetic individuals. TTR expression was particularly seen in alpha (glucagon) cells. Islets from type-2 diabetic patients had proportionally more transthyretin-reactive islet cells, including beta cells. A weak transthyretin immunoreaction in IAPP-derived amyloid occurred in some specimens. In seeding experiments in vitro, we found that TTR fibrils did not seed IAPP while IAPP fibrils seeded TTR. It is suggested that islet expression of transthyretin may be altered in type-2 diabetes.
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Raleigh, Daniel, Xiaoxue Zhang, Benoît Hastoy, and Anne Clark. "The β-cell assassin: IAPP cytotoxicity." Journal of Molecular Endocrinology 59, no. 3 (October 2017): R121—R140. http://dx.doi.org/10.1530/jme-17-0105.
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Islet amyloid polypeptide (IAPP) forms cytotoxic oligomers and amyloid fibrils in islets in type 2 diabetes (T2DM). The causal factors for amyloid formation are largely unknown. Mechanisms of molecular folding and assembly of human IAPP (hIAPP) into β-sheets, oligomers and fibrils have been assessed by detailed biophysical studies of hIAPP and non-fibrillogenic, rodent IAPP (rIAPP); cytotoxicity is associated with the early phases (oligomers/multimers) of fibrillogenesis. Interaction with synthetic membranes promotes β-sheet assembly possibly via a transient α-helical molecular conformation. Cellular hIAPP cytotoxicity can be activated from intracellular or extracellular sites. In transgenic rodents overexpressing hIAPP, intracellular pro-apoptotic signals can be generated at different points in β-cell protein synthesis. Increased cellular trafficking of proIAPP, failure of the unfolded protein response (UPR) or excess trafficking of misfolded peptide via the degradation pathways can induce apoptosis; these data indicate that defects in intracellular handling of hIAPP can induce cytotoxicity. However, there is no evidence for IAPP overexpression in T2DM. Extracellular amyloidosis is directly related to the degree of β-cell apoptosis in islets in T2DM. IAPP fragments, fibrils and multimers interact with membranes causing disruption in vivo and in vitro. These findings support a role for extracellular IAPP in β-sheet conformation in cytotoxicity. Inhibitors of fibrillogenesis are useful tools to determine the aberrant mechanisms that result in hIAPP molecular refolding and islet amyloidosis. However, currently, their role as therapeutic agents remains uncertain.
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NAKAZATO, Masamitsu, and Shigeru MATSUKURA. "New Type of Amyloidosis. Islet Amyloid Polypeptide(IAPP/Amylin) in Non-Insulin-Dependent Diabetes Mellitus." Internal Medicine 32, no. 12 (1993): 928–29. http://dx.doi.org/10.2169/internalmedicine.32.928.
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Tomasello, Marianna Flora, Alessandro Sinopoli, and Giuseppe Pappalardo. "On the Environmental Factors Affecting the Structural and Cytotoxic Properties of IAPP Peptides." Journal of Diabetes Research 2015 (2015): 1–15. http://dx.doi.org/10.1155/2015/918573.
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Pancreatic islets in type 2 diabetes mellitus (T2DM) patients are characterized by reducedβ-cells mass and diffuse extracellular amyloidosis. Amyloid deposition involves the islet amyloid polypeptide (IAPP), a neuropancreatic hormone cosecreted with insulin byβ-cells. IAPP is physiologically involved in glucose homeostasis, but it may turn toxic toβ-cells owing to its tendency to misfold giving rise to oligomers and fibrils. The process by which the unfolded IAPP starts to self-assemble and the overall factors promoting this conversion are poorly understood. Other open questions are related to the nature of the IAPP toxic species and how exactlyβ-cells die. Over the last decades, there has been growing consensus about the notion that early molecular assemblies, notably small hIAPP oligomers, are the culprit ofβ-cells decline. Numerous environmental factors might affect the conformational, aggregation, and cytotoxic properties of IAPP. Herein we review recent progress in the field, focusing on the influences that membranes, pH, and metal ions may have on the conformational conversion and cytotoxicity of full-length IAPP as well as peptide fragments thereof. Current theories proposed for the mechanisms of toxicity will be also summarized together with an outline of the underlying molecular links between IAPP and amyloid beta (Aβ) misfolding.
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Nguyen, Phuong Trang, Nagore Andraka, Carole Anne De Carufel, and Steve Bourgault. "Mechanistic Contributions of Biological Cofactors in Islet Amyloid Polypeptide Amyloidogenesis." Journal of Diabetes Research 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/515307.
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Type II diabetes mellitus is associated with the deposition of fibrillar aggregates in pancreatic islets. The major protein component of islet amyloids is the glucomodulatory hormone islet amyloid polypeptide (IAPP). Islet amyloid fibrils are virtually always associated with several biomolecules, including apolipoprotein E, metals, glycosaminoglycans, and various lipids. IAPP amyloidogenesis has been originally perceived as a self-assembly homogeneous process in which the inherent aggregation propensity of the peptide and its local concentration constitute the major driving forces to fibrillization. However, over the last two decades, numerous studies have shown a prominent role of amyloid cofactors in IAPP fibrillogenesis associated with the etiology of type II diabetes. It is increasingly evident that the biochemical microenvironment in which IAPP amyloid formation occurs and the interactions of the polypeptide with various biomolecules not only modulate the rate and extent of aggregation, but could also remodel the amyloidogenesis process as well as the structure, toxicity, and stability of the resulting fibrils.
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Fortin, Jessica S., and Marie-Odile Benoit-Biancamano. "Inhibition of islet amyloid polypeptide aggregation and associated cytotoxicity by nonsteroidal anti-inflammatory drugs." Canadian Journal of Physiology and Pharmacology 94, no. 1 (January 2016): 35–48. http://dx.doi.org/10.1139/cjpp-2015-0117.
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Nonsteroidal anti-inflammatory drugs (NSAIDs) constitute an important pharmacotherapeutic class that, over the past decade, have expanded in application to a panoply of medical conditions. They have been tested for neurodegenerative diseases such as Alzheimer’s to reduce inflammation and also in the attempt to abrogate amyloid deposition. However, the use of NSAIDs as aggregation inhibitors has not been extensively studied in pancreatic amyloid deposition. Pancreatic amyloidosis involves the misfolding of islet amyloid polypeptide (IAPP) and contributes to the progression of type-2 diabetes in humans and felines. To ascertain their antiamyloidogenic activity, several NSAIDs were tested using fluorometric thioflavin-T assays, circular dichroism, photo-induced cross-linking assays, and cell culture. Celecoxib, diclofenac, indomethacin, meloxicam, niflumic acid, nimesulide, phenylbutazone, piroxicam, sulindac, and tenoxicam reduced fibrillization at a molar ratio of 1:10. The circular dichroism spectra of diclofenac, piroxicam, and sulindac showed characteristic spectral signatures found in predominantly α-helical structures. The oligomerization of human IAPP was abrogated with diclofenac and sulindac at a molar ratio of 1:5. The cytotoxic effects of pre-incubated human IAPP on cultured INS-1 cells were noticeably reduced in the presence of diclofenac, meloxicam, phenylbutazone, sulindac, and tenoxicam at a molar ratio of 1:10. Our results demonstrate that NSAIDs can provide chemical scaffolds to generate new and promising antiamyloidogenic agents that can be used alone or as a coadjuvant therapy.
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Wasana Jayaweera, Sanduni, Solmaz Surano, Nina Pettersson, Elvira Oskarsson, Lovisa Lettius, Anna L. Gharibyan, Intissar Anan, and Anders Olofsson. "Mechanisms of Transthyretin Inhibition of IAPP Amyloid Formation." Biomolecules 11, no. 3 (March 10, 2021): 411. http://dx.doi.org/10.3390/biom11030411.
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Amyloid-formation by the islet amyloid polypeptide (IAPP), produced by the β-cells in the human pancreas, has been associated with the development of type II diabetes mellitus (T2DM). The human plasma-protein transthyretin (TTR), a well-known amyloid-inhibiting protein, is interestingly also expressed within the IAPP producing β-cells. In the present study, we have characterized the ability of TTR to interfere with IAPP amyloid-formation, both in terms of its intrinsic stability as well as with regard to the effect of TTR-stabilizing drugs. The results show that TTR can prolong the lag-phase as well as impair elongation in the course of IAPP-amyloid formation. We also show that the interfering ability correlates inversely with the thermodynamic stability of TTR, while no such correlation was observed as a function of kinetic stability. Furthermore, we demonstrate that the ability of TTR to interfere is maintained also at the low pH environment within the IAPP-containing granules of the pancreatic β-cells. However, at both neutral and low pH, the addition of TTR-stabilizing drugs partly impaired its efficacy. Taken together, these results expose mechanisms of TTR-mediated inhibition of IAPP amyloid-formation and highlights a potential therapeutic target to prevent the onset of T2DM.
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Pithadia, Amit, Jeffrey R. Brender, Carol A. Fierke, and Ayyalusamy Ramamoorthy. "Inhibition of IAPP Aggregation and Toxicity by Natural Products and Derivatives." Journal of Diabetes Research 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/2046327.
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Fibrillar aggregates of human islet amyloid polypeptide, hIAPP, a pathological feature seen in some diabetes patients, are a likely causative agent for pancreatic beta-cell toxicity, leading to a transition from a state of insulin resistance to type II diabetes through the loss of insulin producing beta-cells by hIAPP induced toxicity. Because of the probable link between hIAPP and the development of type II diabetes, there has been strong interest in developing reagents to study the aggregation of hIAPP and possible therapeutics to block its toxic effects. Natural products are a class of compounds with interesting pharmacological properties against amyloids which have made them interesting targets to study hIAPP. Specifically, the ability of polyphenolic natural products, EGCG, curcumin, and resveratrol, to modulate the aggregation of hIAPP is discussed. Furthermore, we have outlined possible mechanistic discoveries of the interaction of these small molecules with the peptide and how they may mitigate toxicity associated with peptide aggregation. These abundantly found agents have been long used to combat diseases for many years and may serve as useful templates toward developing therapeutics against hIAPP aggregation and toxicity.
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Asthana, Shreyasi, Bibekanand Mallick, Andrei T. Alexandrescu, and Suman Jha. "IAPP in type II diabetes: Basic research on structure, molecular interactions, and disease mechanisms suggests potential intervention strategies." Biochimica et Biophysica Acta (BBA) - Biomembranes 1860, no. 9 (September 2018): 1765–82. http://dx.doi.org/10.1016/j.bbamem.2018.02.020.
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Fortin, Jessica S., Marie-Odile Benoit-Biancamano, and René C.-Gaudreault. "Discovery of ethyl urea derivatives as inhibitors of islet amyloid polypeptide fibrillization and cytotoxicity." Canadian Journal of Physiology and Pharmacology 94, no. 3 (March 2016): 341–46. http://dx.doi.org/10.1139/cjpp-2015-0204.
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Islet amyloid polypeptide (IAPP) has been shown to form amyloid deposits in pancreatic islets, thereby furthering type 2 diabetes disease progression. Further discovery of new molecules is needed to create a diverse set of molecules that impede pancreatic amyloidosis. We have recently designed and synthesized N-phenyl-N′-(2-ethyl)ureas (EU) that are non-cytotoxic small molecules, to evaluate the role of the aryl-substituted moiety on the inhibition of hIAPP fibrillization. Several EUs were tested in vitro for their anti-amyloidogenic activity using the fluorometric ThT assay, the photo-induced cross-linking (PIUCP) assay, and cell survival assay in pancreatic MIN-6 cells. EU-362 and EU-418 were able to significantly inhibit the formation of hIAPP fibrils and protected cells from amyloid cytotoxic effects. Our results suggest that increasing the nucleophilic potency of the aryl moiety significantly enhances the anti-amyloidogenic activity of the molecules.
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Yan, Li-Mei, Aleksandra Velkova, Marianna Tatarek-Nossol, Erika Andreetto, and Aphrodite Kapurniotu. "IAPP Mimic Blocks Aβ Cytotoxic Self-Assembly: Cross-Suppression of Amyloid Toxicity of Aβ and IAPP Suggests a Molecular Link between Alzheimer's Disease and Type II Diabetes." Angewandte Chemie International Edition 46, no. 8 (February 12, 2007): 1246–52. http://dx.doi.org/10.1002/anie.200604056.
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De Santis, Emiliano, Emma Shardlow, Francesco Stellato, Olivier Proux, Giancarlo Rossi, Christopher Exley, and Silvia Morante. "X-Ray Absorption Spectroscopy Measurements of Cu-ProIAPP Complexes at Physiological Concentrations." Condensed Matter 4, no. 1 (January 18, 2019): 13. http://dx.doi.org/10.3390/condmat4010013.
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The amyloidogenic islet amyloid polypeptide (IAPP) and the associated pro-peptide ProIAPP1–48 are involved in cell death in type 2 diabetes mellitus. It has been observed that interactions of this peptide with metal ions have an impact on the cytotoxicity of the peptides as well as on their deposition in the form of amyloid fibrils. In particular, Cu(II) seems to inhibit amyloid fibril formation, thus suggesting that Cu homeostasis imbalance may be involved in the pathogenesis of type 2 diabetes mellitus. We performed X-ray Absorption Spectroscopy (XAS) measurements of Cu(II)-ProIAPP complexes under near-physiological (10 μM), equimolar concentrations of Cu(II) and peptide. Such low concentrations were made accessible to XAS measurements owing to the use of the High Energy Resolved Fluorescence Detection XAS facility recently installed at the ESRF beamline BM16 (FAME-UHD). Our preliminary data show that XAS measurements at micromolar concentrations are feasible and confirm that ProIAPP1–48-Cu(II) binding at near-physiological conditions can be detected.
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Fu, Li, Zhuguang Wang, Victor S. Batista, and Elsa C. Y. Yan. "New Insights from Sum Frequency Generation Vibrational Spectroscopy into the Interactions of Islet Amyloid Polypeptides with Lipid Membranes." Journal of Diabetes Research 2016 (2016): 1–17. http://dx.doi.org/10.1155/2016/7293063.
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Studies of amyloid polypeptides on membrane surfaces have gained increasing attention in recent years. Several studies have revealed that membranes can catalyze protein aggregation and that the early products of amyloid aggregation can disrupt membrane integrity, increasing water permeability and inducing ion cytotoxicity. Nonetheless, probing aggregation of amyloid proteins on membrane surfaces is challenging. Surface-specific methods are required to discriminate contributions of aggregates at the membrane interface from those in the bulk phase and to characterize protein secondary structuresin situand in real time without the use of perturbing spectroscopic labels. Here, we review the most recent applications of sum frequency generation (SFG) vibrational spectroscopy applied in conjunction with computational modeling techniques, a joint experimental and computational methodology that has provided valuable insights into the aggregation of islet amyloid polypeptide (IAPP) on membrane surfaces. These applications show that SFG can provide detailed information about structures, kinetics, and orientation of IAPP during interfacial aggregation, relevant to the molecular mechanisms of type II diabetes. These recent advances demonstrate the promise of SFG as a new approach for studying amyloid diseases at the molecular level and for the rational drug design targeting early aggregation products on membrane surfaces.
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Neddenriep, Bradley, Anastasia Calciano, Daniel Conti, Erin Sauve, Marissa Paterson, Edward Bruno, and David A. Moffet. "Short Peptides as Inhibitors of Amyloid Aggregation." Open Biotechnology Journal 5, no. 1 (December 23, 2011): 39–46. http://dx.doi.org/10.2174/1874070701105010039.
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The misfolding and aggregation of proteins into amyloid has been linked to a variety of age-related diseases. Aggregation of proteins, such as Aβ in Alzheimer's disease and Islet Amyloid Polypeptide (IAPP, amylin) in type 2 diabetes, appears to lead to the formation of toxic assemblies. These assemblies range in size from small oligomers (2-8 proteins) to large fibrils (thousands of proteins). It remains unclear how these amyloidogenic proteins misfold and form toxic species, but growing evidence suggests that inhibiting the aggregation of these proteins could slow, if not prevent altogether, the progression of these diseases. We describe the use of small peptides (<43 amino acids) as inhibitors of amyloid- based aggregation. These peptides, often short complementary segments of the amyloid proteins, can be useful (i) for identifying the aggregation-prone regions of the amyloid proteins (ii) as models for drug discovery and (iii) as potential therapeutic agents themselves.
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Bell, Phoenix D., Aaron R. Huber, and Tom C. DeRoche. "Along for the Ride: Intrahepatic Cholangiocarcinoma with Concomitant LECT2 Amyloidosis." Case Reports in Pathology 2020 (July 17, 2020): 1–4. http://dx.doi.org/10.1155/2020/8830763.
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We present a case of a 69-year-old Hispanic male with a past medical history of type II diabetes mellitus who presented with a two-month history of abdominal pain. A CT scan was performed which identified a liver mass. Biopsy of the liver mass revealed infiltration of normal liver parenchyma by atypical glands surrounded by pale eosinophilic material. The atypical glands were positive for CK7, while negative for CK20, CDX-2, and TTF-1, consistent with intrahepatic cholangiocarcinoma. A Congo red stain was performed, which highlighted salmon-orange areas, some with a globular appearance, around the glands and within the sinusoids and vasculature. Under polarized light, these areas displayed apple-green birefringence. These findings were consistent with amyloidosis, which was further supported by identification of ALECT2- (leukocyte chemotactic factor-2-) type amyloid on mass spectrometry. To our knowledge, this is the first documented case of intrahepatic cholangiocarcinoma arising in association with LECT2 amyloidosis.
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K.J. Kinnunen, Paavo. "Amyloid Formation on Lipid Membrane Surfaces." Open Biology Journal 2, no. 1 (December 31, 2009): 163–75. http://dx.doi.org/10.2174/1874196700902010163.
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Several lines of research have concluded lipid membranes to efficiently induce the formation of amyloid-type fibers by a number of proteins. In brief, membranes, particularly when containing acidic, negatively charged lipids, concentrate cationic peptides/proteins onto their surfaces, into a local low pH milieu. The latter together with the anisotropic low dielectricity environment of the lipid membrane further forces polypeptides to align and adjust their conformation so as to enable a proper arrangement of the side chains according to their physicochemical characteristics, creating a hydrophobic surface contacting the lipid hydrocarbon region. Concomitantly, the low dielectricity also forces the polypeptides to maximize intramolecular hydrogen bonding by folding into amphipathic α-helices, which further aggregate, the latter adding cooperativity to the kinetics of membrane association. After the above, fast first events, several slower, cooperative conformational transitions of the oligomeric polypeptide chains take place in the membrane surface. Relaxation to the free energy minimum involves a complex free energy landscape of the above system comprised of a soft membrane interacting with, and accommodating peptide polymers. The overall free energy landscape thus involves a region of polypeptide aggregation associated with folding: polypeptide physicochemical properties and available conformation/oligomerization state spaces as determined by the amino acid sequence. In this respect, of major interest are those natively disordered proteins interacting with lipids, which in the absence of a ligand have no inherent structure and may adapt different functional states. Key sequence features for lipid and membrane interactions from the point of view of amyloid formation are i) conformational ambiguity, ii) adoption of amphipathic structures, iii) ion binding, and iv) propensity for aggregation and amyloid fibrillation. The pathways and states of the polypeptide conformational transitions further depend on the lipid composition, which thus couples the inherent properties of lipid membranes to the inherent properties of proteins. In other words, different lipids and their mixtures generate a very complex and rich scale of environments, involving also a number of cooperative transitions, sensitive to exogenous factors (temperature, ions, pH, small molecules), with small scale molecular properties and interactions translating into large scale 2- and 3-D organization. These lipid surface properties and topologies determine and couple to the transitions of the added polypeptide, the latter now undergoing oligomerization, with a sequence of specific and cooperative conformational changes. The above aggregation/folding pathways and transient intermediates of the polypeptide oligomers appear to have distinct biological functions. The latter involve i) the control of enzyme catalytic activity, ii) cell defence (e.g. antimicrobial and cancer killing peptides/proteins, as well as possibly also iii) control of cell shape and membrane traffic. On the other hand, these processes are also associated with the onset of major sporadic diseases, all involving protein misfolding, aggregation and amyloid formation, such as in Alzheimer’s and Parkinson’s diseases, prion disease, and type 2 diabetes. Exemplified by the latter, in an acidic phospholipid containing membrane human islet associated polypeptide (IAPP or amylin, secreted by pancreatic β-cells) efficiently transforms into amyloid β-sheet fibrils, the latter property being associated with established sequence features of IAPP, involved in aggregation and amyloid formation. IAPP sequence also harbors anion binding sites, such as those involving cationic side chains and N-terminal NH-groups of the α-helix. The association with acidic lipids neutralizes ‘gatekeeping’ cationic residues, abrogating electrostatic peptide-peptide repulsion. The subsequent aggregation of the α-helices involves further oligomerization and a sequence of slow transitions, driven by hydrogen bonding, and ending up as amyloid β-sheet fibrils. Importantly, the above processing of IAPP in its folding/aggregation free energy landscape under the influence of a lipid membrane involves also transient cytotoxic intermediates, which permeabilize membranes, allowing influx of Ca2+ and triggering of cell death, this process resulting in the loss of β-cells, seen in type 2 diabetes. Similar chains of events are believed to underlie the loss of tissue function in the other disorders mentioned above.
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SARIDOMICHELAKIS (Μ. Ν. ΣΑΡΙΔΟΜΙΧΕΛΑΚΗΣ), M. N., and A. F. KOUTINAS (Α.Φ. ΚΟΥΤΙΝΑΣ). "Etiopathogenesis and clinical manifestations of the non-ketotic feline diabetes mellitus." Journal of the Hellenic Veterinary Medical Society 55, no. 3 (December 6, 2017): 262. http://dx.doi.org/10.12681/jhvms.15112.
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Diabetes mellitus, the clinical syndrome that results form absolute or relative insulin deficiency and/or reduced number or sensitivity of the insulin receptors, is considered one of the most common endocrine diseases in the cat, being secondary only to hypethyroidism. The exact etiology of type I feline diabetes mellitus remains obscure, although in many cases occurs secondarily to chronic pancreatitis. Type II diabetes mellitus, which is very common in the everyday clinical practice, is characterized by relative insulin deficiency, secondary to reduced production of this hormone (chronic pancreatitis, pancreatic amyloidosis), insulin resistance and/or increased glucose production by the liver (obesity, chronic stress, overproduction of amylin). Secondary (type III) diabetes mellitus is the result of various causes, not directly involving pancreatic tissue, that cause insulin resistance, such as hyperadrenocorticism, pheochromocytoma, acromegaly, hyperthyroidism, infections, neoplasia, hyperlipidemia, chronic heart and renal failure and the exogenous administration of glucocorticoids and progestagens. The most common clinical manifestations of feline non-ketotic diabetes mellitus include polyuria, polydipsia, polyphagia, weight loss, hepatomegaly, retinopathy, peripheral polyneuropathy, dry seborrhea and those resulting form the secondary infections, such as cystitis and stomatitis.
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Prabhu, M. P. Taraka, and Nandini Sarkar. "Quantum Dots as Promising Theranostic Tools Against Amyloidosis: A Review." Protein & Peptide Letters 26, no. 8 (September 11, 2019): 555–63. http://dx.doi.org/10.2174/0929866526666181212113855.
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Amyloids are highly ordered beta sheet rich stable protein aggregates, which have been found to play a significant role in the onset of several degenerative diseases such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, Type II diabetes mellitus and so on. Aggregation of proteins leading to amyloid fibril formation via intermediate(s), is thought to be a nucleated condensation polymerization process associated with many pathological conditions. There has been extensive research to identify inhibitors of these disease oriented aggregation processes. In recent times, quantum dots, with their unique physico-chemical properties have grabbed the attention of scientific community due to its applications in medical sciences. Quantum dots are nano-particles usually made of semiconductor materials which emit fluorescence upon radiation. The wavelength of fluorescence emission varies with changes in size of quantum dots. Several studies have reported significant inhibitory effects of these quantum dots towards amyloidogenesis, thereby presenting themselves as promising candidates against amyloidosis. Further, studies have also revealed amyloid detection capacity of quantum dots with sensitivity and specificity better than conventional probes. In the current review, we will discuss the various effects of quantum dots on protein aggregation pathways, their mechanism of actions and their potentials as effective therapeutics against amyloidosis.
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Scollo, Federica, and Carmelo La Rosa. "Amyloidogenic Intrinsically Disordered Proteins: New Insights into Their Self-Assembly and Their Interaction with Membranes." Life 10, no. 8 (August 8, 2020): 144. http://dx.doi.org/10.3390/life10080144.
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Aβ, IAPP, α-synuclein, and prion proteins belong to the amyloidogenic intrinsically disordered proteins’ family; indeed, they lack well defined secondary and tertiary structures. It is generally acknowledged that they are involved, respectively, in Alzheimer’s, Type II Diabetes Mellitus, Parkinson’s, and Creutzfeldt–Jakob’s diseases. The molecular mechanism of toxicity is under intense debate, as many hypotheses concerning the involvement of the amyloid and the toxic oligomers have been proposed. However, the main role is represented by the interplay of protein and the cell membrane. Thus, the understanding of the interaction mechanism at the molecular level is crucial to shed light on the dynamics driving this phenomenon. There are plenty of factors influencing the interaction as mentioned above, however, the overall view is made trickier by the apparent irreproducibility and inconsistency of the data reported in the literature. Here, we contextualized this topic in a historical, and even more importantly, in a future perspective. We introduce two novel insights: the chemical equilibrium, always established in the aqueous phase between the free and the membrane phospholipids, as mediators of protein-transport into the core of the bilayer, and the symmetry-breaking of oligomeric aggregates forming an alternating array of partially ordered and disordered monomers.
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Bély, M., and Ά. Apáthy. "FRI0090 Atherosclerosis, Hypertension, Adult Type II Diabetes Mellitus and Isolated Amyloidosis Localized to the Islets of Langerhans – A Postmortem Clinicopathologic Statistical Study of 234 Rheumatoid Arthritis Patients:." Annals of the Rheumatic Diseases 74, Suppl 2 (June 2015): 452.2–452. http://dx.doi.org/10.1136/annrheumdis-2015-eular.1371.
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Shatzel, Joseph J., Rebecca Wang, Regina C. Lee, Saurabh Malhotra, Kabir Mody, Deborah L. Ornstein, and Christopher H. Lowrey. "Uncovering a Covert Enemy: Systemic AL Amyloidosis Associated With Intravascular Diffuse Large B-Cell Lymphoma." Blood 122, no. 21 (November 15, 2013): 5066. http://dx.doi.org/10.1182/blood.v122.21.5066.5066.
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Abstract Introduction AL amyloidosis, precipitated by the deposition of immunoglobulin light chains in various organs, is generally secondary to the benign or malignant proliferation of clonal plasma cells. Reviews from large amyloid centers show that approximately 2-3% of AL amyloidosis is associated with an underlying non-Hodgkin lymphoma (NHL). Of the non-Hodgkin lymphomas, lymphoplasmacytic lymphoma (LPL) is most commonly associated with systemic AL amyloidosis. Systemic NHL-associated AL amyloidosis tends to feature a high level of IgM paraproteinemia and a predilection for several different organ tropisms. Here we report the unique case of a 71-year-old male with an insidious course of hypotension and worsening renal failure of unknown etiology, who was ultimately diagnosed post-mortem with AL amyloidosis associated with an intravascular large B-cell lymphoma (IVLBCL). Case Description A 71-year-old white male presented to the hospital after a fall. His medical history included type II diabetes, spinal stenosis, and a 30-pack-year smoking history. Over the past few months, he noticed a steady decline in functional status. On admission, he was hypotensive with bilateral 2+ pitting lower extremity edema. Laboratory evaluation revealed leukocytosis, anemia, and acute kidney injury with elevated creatinine and blood urea nitrogen. Urinalysis showed 30 mg/dL of protein, along with the presence of white and red blood cells and moderate bacteria. Enterococcus was subsequently cultured from the urine. A chest X-ray revealed small bilateral effusions. The patient was treated for urosepsis with antibiotics and vasopressor support in the intensive care unit. His hypotension improved initially, but over the next 3 weeks his course was complicated by recurrent episodes of hypotension, altered mental status, and worsening renal function. An exhaustive laboratory workup was negative for infection, and a transthoracic echocardiogram showed no significant findings. Further evaluation included a normal cortisol stimulation test and TSH level, but a serum protein electrophoresis showed 0.13 g/dL of monoclonal IgM lambda immunoglobulin (Figure A) with a urine protein electrophoresis showing a low level of lambda free light chains. Abdominal fat pad biopsy was negative for amyloid. The patient's condition continued to deteriorate, and he died on hospital day 29 with no clear diagnosis. Post-mortem examination revealed a CD20+, lambda restricted intravascular diffuse large B-cell lymphoma involving the kidneys, prostate, a cecal polyp, and lungs (Figure B). Sections of lung tissue revealed scattered areas of extracellular eosinophilic material that stained brick red with Congo red staining (Figure C) and displayed apple green birefringence under polarized light (Figure D). Similar findings in the heart and kidneys were consistent with systemic amyloidosis. Bone marrow analysis showed normal trilineage hematopoiesis with no evidence for involvement by lymphoma or plasma cell neoplasm. Discussion This case exhibits the first reported association of two rare and diagnostically challenging disorders: intravascular large B-cell lymphoma (IVLBCL) and systemic AL amyloidosis. Patients with IVLBCL often present with nonspecific symptoms secondary to small vessel occlusion and subacute deterioration in performance status, as was the case with our patient. Our patient's underlying intravascular NHL with systemic AL amyloidosis proved difficult to diagnose with his low-level IgM paraproteinemia serving as the only clue to the cause of his illness. The negative fat pad biopsy added to the diagnostic difficulty, but was not surprising due to the low sensitivity of the test in detecting systemic amyloidosis. In addition, diagnosing intravascular lymphoma is difficult as patients present with nonspecific findings and often without lymphadenopathy, making post-mortem diagnosis common. Thus, this case sets a precedent for intravascular diffuse large B-cell lymphoma provoking the onset of systemic AL amyloidosis – a covert, morbid, and diagnostically challenging combination. Disclosures: No relevant conflicts of interest to declare.
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Rapsinski, Glenn J., Meghan A. Wynosky-Dolfi, Gertrude O. Oppong, Sarah A. Tursi, R. Paul Wilson, Igor E. Brodsky, and Çagla Tükel. "Toll-Like Receptor 2 and NLRP3 Cooperate To Recognize a Functional Bacterial Amyloid, Curli." Infection and Immunity 83, no. 2 (November 24, 2014): 693–701. http://dx.doi.org/10.1128/iai.02370-14.
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Amyloids are proteins with cross-β-sheet structure that contribute to pathology and inflammation in complex human diseases, including Alzheimer's disease, Parkinson's disease, type II diabetes, and secondary amyloidosis. Bacteria also produce amyloids as a component of their extracellular matrix during biofilm formation. Recently, several human amyloids were shown to activate the NLRP3 inflammasome, leading to the activation of caspase 1 and production of interleukin 1β (IL-1β). In this study, we investigated the activation of the NLRP3 inflammasome by bacterial amyloids using curli fibers, produced bySalmonella entericaserovar Typhimurium andEscherichia coli. Here, we show that curli fibers activate the NLRP3 inflammasome, leading to the production of IL-1β via caspase 1 activation. Investigation of the underlying mechanism revealed that activation of Toll-like receptor 2 (TLR2) by curli fibers is critical in the generation of IL-1β. Interestingly, activation of the NLRP3 inflammasome by curli fibers or by amyloid β of Alzheimer's disease does not cause cell death in macrophages. Overall, these data identify a cross talk between TLR2 and NLRP3 in response to the bacterial amyloid curli and generation of IL-1β as a product of this interaction.
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Sirangelo, Ivana, and Clara Iannuzzi. "Understanding the Role of Protein Glycation in the Amyloid Aggregation Process." International Journal of Molecular Sciences 22, no. 12 (June 21, 2021): 6609. http://dx.doi.org/10.3390/ijms22126609.
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Protein function and flexibility is directly related to the native distribution of its structural elements and any alteration in protein architecture leads to several abnormalities and accumulation of misfolded proteins. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidosis characterized by the accumulation of amyloid aggregates both in the extracellular space of tissues and as intracellular deposits. Post-translational modifications are known to have an active role in the in vivo amyloid aggregation as able to affect protein structure and dynamics. Among them, a key role seems to be played by non-enzymatic glycation, the most unwanted irreversible modification of the protein structure, which strongly affects long-living proteins throughout the body. This study provided an overview of the molecular effects induced by glycation on the amyloid aggregation process of several protein models associated with misfolding diseases. In particular, we analyzed the role of glycation on protein folding, kinetics of amyloid formation, and amyloid cytotoxicity in order to shed light on the role of this post-translational modification in the in vivo amyloid aggregation process.
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Fürnsinn, Clemens, Martin Komjati, Ole D. Madsen, Barbara Schneider, and Werner Waldhäusl. "Histochemical changes in pancreatic islets obtained from obese Zucker rats (fa/fa) on a diabetogenic diet. No evidence for non-enzymatic protein glycation in endocrine cells." Acta Endocrinologica 129, no. 1 (July 1993): 46–53. http://dx.doi.org/10.1530/acta.0.1290046.
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Genetically obese Zucker rats (fa/fa) on a diabetogenic diet rich in lard and sucrose develop chronic hyperglycemia accompanied by severe hyperinsulinemia. Non-enzymatically glycated protein content was increased in tendon (p<0.0001) and aorta (p<0.04), but not nerve, from hyperglycemic rats as compared to normoglycemic lean litter-mates on a conventional chow diet (mmol furosine/mol tyrosine in tissue hydrolysate from 61-week-old rats: tendon, 29.8±1.8 vs 25.9±1.3; aorta, 12.0±1.0 vs 11.0±1.1). In pancreatic islets, non-enzymatically glycated protein was neither found in lean rats of any age nor in the obese up to an age of 36 weeks. At an age of 61 weeks, non-enzymatically glycated protein accumulated in islets of obese animals, resulting in levels of 17.02–44.65 mmol furosine/mol tyrosine. This rise in islet glycated protein content was not accompanied by a comparable increase in plasma glycemia, but simultaneous histological examination of pancreatic tissue revealed fibrosis of islets. Fibers were probably of collagenic quality without islet amyloid polypeptide immunoreactivity. Because collagen is known to be highly susceptible to non-enzymatic glycation, we suspect that collagenic fibers but not endocrine cells are the main source of glycated protein accumulation in these islets. Hence, our data do not give evidence that non-enzymatic protein glycation plays a role in the islet degeneration occurring in hyperglycemia. Furthermore, immunohistochemical staining for various endocrine peptides did not suggest loss of any hormone-producing cell type or defective pancreatic hormone production in hyperglycemic old, obese Zucker rats. The more soluble nature of rat vs human islet amyloid polypeptide may explain the fact that hyperglycemia-induced fibrosis in rat islets does not include amyloidosis, which may contribute to late beta cell failure in human type II diabetes.
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Barton, Jeremy, D. Sebastian Arias, Chamani Niyangoda, Gustavo Borjas, Nathan Le, Saefallah Mohamed, and Martin Muschol. "Kinetic Transition in Amyloid Assembly as a Screening Assay for Oligomer-Selective Dyes." Biomolecules 9, no. 10 (September 27, 2019): 539. http://dx.doi.org/10.3390/biom9100539.
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Assembly of amyloid fibrils and small globular oligomers is associated with a significant number of human disorders that include Alzheimer’s disease, senile systemic amyloidosis, and type II diabetes. Recent findings implicate small amyloid oligomers as the dominant aggregate species mediating the toxic effects in these disorders. However, validation of this hypothesis has been hampered by the dearth of experimental techniques to detect, quantify, and discriminate oligomeric intermediates from late-stage fibrils, in vitro and in vivo. We have shown that the onset of significant oligomer formation is associated with a transition in thioflavin T kinetics from sigmoidal to biphasic kinetics. Here we showed that this transition can be exploited for screening fluorophores for preferential responses to oligomer over fibril formation. This assay identified crystal violet as a strongly selective oligomer-indicator dye for lysozyme. Simultaneous recordings of amyloid kinetics with thioflavin T and crystal violet enabled us to separate the combined signals into their underlying oligomeric and fibrillar components. We provided further evidence that this screening assay could be extended to amyloid-β peptides under physiological conditions. Identification of oligomer-selective dyes not only holds the promise of biomedical applications but provides new approaches for unraveling the mechanisms underlying oligomer versus fibril formation in amyloid assembly.
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M, Bély, and Apáthy A. "β-cell Related Amyloidosis Localized to the Islets of Langerhans, Type II Diabetes Mellitus and Liponecrotic Pancreatitis in Rheumatoid Arthritis: A Postmortem Clinicopathologic Statistical Study of 234 Autopsy Patients." Integrative Diabetes and Cardiovascular Diseases, April 18, 2019, 94–110. http://dx.doi.org/10.18314/idcd.v3i1.1573.
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The aim of this study was to determine the prevalence of systemic AA amyloidosis (AAa), islet amyloidosis (IA) and liponecrotic pancreatitis (LnP) including acute liponecrotic (aLnP), acute relapsing liponecrotic (aRelLnP), and chronic liponecrotic pancreatitis (chrLnP) in rheumatoid arthritis (RA), and to analyse the possible relationship between them.Patients and methods: At the National Institute of Rheumatology 11558 patients died between 1969 and 1998; among them 234 with RA, and all of them were autopsied. RA was confirmed clinically according to the criteria of the American College of Rheumatology (ACR). The diagnosis of DM was based on clinical data. Tissue samples of pancreas were available for histologic evaluation in 164 of 234 patients. AAa, IA and LnP were diagnosed histologically. Demographics of different patient cohorts were compared with the Student (Welch) t probe. The relationships between AAa and IA, furthermore between IA and DM or LnP (including aLnP, aRelLnP, chrLnP) were analyzed by Pearson’s chi-squared (c2) test.Results: AAa complicated RA in 42 (25.61%) of 164 patients. IA localized to the islets of Langerhans was observed in 16 (9.76%) of 164 pancreases. Clinically diagnosed DM was associated with RA in 31 (18.90%) of 164 patients. Pancreatitis with multiple liponecrotic foci (LnP) was found in 19 (11.58%) of 164 patients; aLnP existed in 9 (47.37%), aRelLnP in 4 (21.05%), and liponecrotic foci in combination with chronic fibrotic pancreatitis (chrLnP) in 6 (31.58%) of these 19 patients.Discussion and conclusions: There was no significant difference between female and male RA patients associated with AAa, IA, DM and LnP. The age, sex and onset of disease did not influence basically the prevalence of AAa, IA, DM and LnP except male patients with IA, whose mean age at death was significantly higher than the general RA population. IA (fibrillar amyloid IAPP deposits -AIAPP) is related to the activity of b cells and may presumably be a faulty product of b-cells (normal islets of Langerhans do not contain IA deposits). The progressive deposition of IAPP prohormon fragments inhibits the function of b-cells because of their toxic effect and/or blocking mechanically the blood supply of b-cells and they “die in their own product”. The significant correlation between IA and DM refers to a close connection between them, but not necessarily a direct cause and effect relationship; it may be an indirect result of damaged (apoptotic) b-cells. The early stage of IA is characterized by minimal IAPP deposits involving only a few islets, which represents a clinically latent DM, and the advanced stage of IA is characterized by massive IAPP deposits involving most of the islets, which correspond to clinically manifest DM. Based on the positive and significant correlation between IA and clinically not diagnosed DM, IA may be a good indicator of potential DM in the latent stage of disease. Therefore we recommend that all biopsy material and surgical specimens of pancreas to be tested for IA or IAPP deposition.
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Christensen, Mikkel, Nils A. Berglund, and Birgit Schiøtt. "The Effect of Cholesterol on Membrane-Bound Islet Amyloid Polypeptide." Frontiers in Molecular Biosciences 8 (April 22, 2021). http://dx.doi.org/10.3389/fmolb.2021.657946.
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Islet amyloid polypeptide (IAPP) is a proposed cause of the decreased beta-cell mass in patients with type-II diabetes. The molecular composition of the cell-membrane is important for regulating IAPP cytotoxicity and aggregation. Cholesterol is present at high concentrations in the pancreatic beta-cells, and in-vitro experiments have indicated that it affects the amyloid formation of IAPP either by direct interactions or by changing the properties of the membrane. In this study we apply atomistic, unbiased molecular dynamics simulations at a microsecond timescale to investigate the effect of cholesterol on membrane bound IAPP. Simulations were performed with various combinations of cholesterol, phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. In all simulations, the helical structure of monomer IAPP was stabilized by the membrane. We found that cholesterol decreased the insertion depth of IAPP compared to pure phospholipid membranes, while PS lipids counteract the effect of cholesterol. The aggregation propensity has previously been proposed to correlate with the insertion depth of IAPP, which we found to decrease with the increased ordering of the lipids induced by cholesterol. Cholesterol is depleted in the vicinity of IAPP, and thus our results suggest that the effect of cholesterol is indirect.
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Sarkar, Nandini, Vidyalatha Kolli, Taraka Prabhu MP, Arbin Basak, and Hitesh Mandal. "Inhibitory as well as disaggregation potential of selected hydroxy benzoic phytochemicals on hen egg white lysozyme amyloidogenesis." Current Proteomics 17 (July 29, 2020). http://dx.doi.org/10.2174/1570164617999200729161846.
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Background: Amyloids are a class of ordered protein aggregates which have been implicated in the onset of several degenerative diseases such as Alzheimer's disease, Parkinson's disease, Type II diabetes and so on. Despite extensive research, the exact mechanism and the driving factors for the amyloidogenesis process remain elusive. Identifying molecules which can effectively inhibit and/or disaggregate the fibrils may be one effective therapeutic strategy against amyloidosis Objectives: In the current study, few hydroxy-benzoic phytochemicals were selected to study their effects on formation as well as disaggregation of hen egg white lysozyme (HEWL) amyloids, namely gallic acid, syringic acid, vanillic acid and iso-vanillic acid. Method: Amyloidogenesis was monitored using methods like the thioflavin T assay, field emission scanning electron mi-croscopy (FESEM) and dynamic light scattering (DLS) studies. Further protein conformational changes were monitored us-ing methods like 8-Anilino-naphthalene-1-sulfonate (ANS) fluorescence, circular dichroism (CD) spectroscopy and guani-dine hydrochloride mediated stability studies. Computational approach was also employed to get an insight on the interac-tion(s) between the selected compounds and HEWL using docking studies Result: The selected compounds exhibited significant inhibitory as well as disaggregation effects on HEWL amyloids. In-teraction with the phytochemicals was also associated with considerable conformational changes in HEWL. Docking studies show role of hydrogen bonding between HEWL and the phytochemicals. Conclusion: Thus the current study throws light on the key factors that drive amyloid formation and hence will be helpful for development of effective therapeutics against amyloidosis.