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Shreyasi Asthana, Bibekanand Mallick, Andrei T Alexandrescu, Suman Jha
Islet amyloid polypeptide (a.k.a. IAPP, amylin) is a 37 amino acid hormone that has long been associated with the progression of type II diabetes mellitus (TIIDM) disease. The endocrine peptide hormone aggregatively misfolds to form amyloid deposits in and around the pancreatic islet β-cells that synthesize both insulin and IAPP, leading to a decrease in β-cell mass in patients with the disease. Extracellular IAPP amyloids induce β-cell death through the formation of reactive oxygen species, mitochondrial dysfunction, chromatin condensation, and apoptotic mechanisms, although the precise roles of IAPP in TIIDM are yet to be established...
March 5, 2018: Biochimica et Biophysica Acta
Kayla M Pate, Brandon J Kim, Eric V Shusta, Regina M Murphy
β-amyloid (Aβ) aggregation is causally linked to neuronal pathology in Alzheimer's disease; therefore, several small molecules, antibodies, and peptides have been tested as anti-Aβ agents. We developed two compounds based on the Aβ-binding domain of transthyretin (TTR), a cyclic peptide cG8 and an engineered protein mTTR, and compared them for therapeutically relevant properties. Both mTTR and cG8 inhibit fibrillogenesis of Aβ, with mTTR inhibiting at a lower concentration than cG8. Both inhibit aggregation of amylin but not of α-synuclein...
March 7, 2018: ChemMedChem
Shreyasi Asthana, Mousumi Sahu, Parth Sarathi Nayak, Bibekanand Mallick, Suman Jha
The diminishing β-cell mass of pancreas in type II diabetes mellitus (TIIDM) is intricately linked with high fibrillation propensity of islet amyloid polypeptide (IAPP, aka amylin). IAPP is one of the most amyloidogenic peptide secreted by pancreatic β-cells. In the autopsy of TIIDM patients, IAPP rich amyloid plaques are found containing different components of extracellular matrix (ECM), including heparin. For a positively charged IAPP, interaction with heparin which has accessible high density negatively charged functional groups is anticipated to moderate the fibrillation kinetics...
March 2, 2018: International Journal of Biological Macromolecules
Gitanjali Srivastava, Caroline Apovian
PURPOSE OF REVIEW: Obesity is a global health crisis with detrimental effects on all organ systems leading to worsening disease state and rising costs of care. Persons with obesity failing lifestyle therapies need to be escalated to appropriate pharmacological treatment modalities, medical devices, and/or bariatric surgery if criteria are met and more aggressive intervention is needed. The progression of severe obesity in the patient population coupled with related co-morbidities necessitates the development of novel therapies for the treatment of obesity...
March 5, 2018: Current Obesity Reports
Qiushan Tao, Haihao Zhu, Xi Chen, Robert A Stern, Neil Kowall, Rhoda Au, Jan Krzysztof Blusztajn, Wei Qiao Qiu
Studies suggest that a single injection of pramlintide, an amylin analog, induces changes in Alzheimer's disease (AD) biomarkers in the blood of AD mouse models and AD patients. The aim of this study was to examine whether a pramlintide challenge combined with a phosphatidylcholine (PC) profile diagnoses of AD and mild cognitive impairment (MCI) better than PC alone. Non-diabetic subjects with cognitive status were administered a single subcutaneous injection of 60 mcg of pramlintide under fasting condition...
2018: Journal of Alzheimer's Disease: JAD
Thomas A Lutz, Bernd Coester, Lynda Whiting, Ambrose A Dunn-Meynell, Christina N Boyle, Sebastien G Bouret, Barry E Levin, Christelle Le Foll
Amylin phosphorylates ERK (p-ERK) in the area postrema (AP) to reduce eating and synergizes with leptin to phosphorylate STAT3 in the arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei, to reduce food intake and body weight. The current studies assessed potential amylin and amylin-leptin ARC/VMN interactions on ERK signaling and their roles in postnatal hypothalamic pathway development. In amylin knockout (KO) mice, the density of agouti-related protein (AgRP) immunoreactive (IR) fibers in the hypothalamic paraventricular nucleus (PVN) was increased, while the density of α-melanocyte stimulating hormone (αMSH) fibers was decreased...
February 21, 2018: Diabetes
László I Gerecsei, András Csillag, Gergely Zachar, Lőrinc Gévai, László Simon, Árpád Dobolyi, Ágota Ádám
The member of synthetic cathinone family, methylenedioxypyrovalerone (MDPV), is a frequently used psychoactive drug of abuse. The objective of our study was to determine the effect of MDPV (administered from the 8th to the 14th day of gestation) on the behavior of neonatal and adolescent mice, as well as its effect on maternal care. We measured maternal care (pup retrieval test, nest building), locomotor activity (open field test), and motor coordination (grip strength test) of dams, whereas on pups we examined locomotor activity at postnatal day 7 and day 21 (open field test) and motor coordination on day 21 (grip strength test)...
2018: Frontiers in Neuroscience
Jeremy J Pruzin, Peter T Nelson, Erin L Abner, Zoe Arvanitakis
Type 2 diabetes (T2D) and Alzheimer disease (AD) are both highly prevalent diseases worldwide, and each is associated with high-morbidity and high-mortality. Numerous clinical studies have consistently shown that T2D confers a two-fold increased risk for a dementia, including dementia attributable to AD. Yet, the mechanisms underlying this relationship, especially non-vascular mechanisms, remain debated. Cerebral vascular disease (CVD) is likely to be playing a role. But increased AD neuropathologic changes (ADNC), specifically neuritic amyloid plaques (AP) and neurofibrillary tangles (NFT), are also posited mechanisms...
February 8, 2018: Neuropathology and Applied Neurobiology
Varun Pathak, Peter R Flatt, Nigel Irwin
Cholecystokinin (CCK) is a hormone secreted from I-cells of the gut, as well as neurons in the enteric and central nervous system, that binds and activates CCK-1 and CCK-2 receptors to mediate its biological actions. To date knowledge relating to the physiological significance of CCK has predominantly focused around induction of short-term satiety. However, CCK has also been highlighted to possess important actions in relation to the regulation of insulin secretion, as well as overall beta-cell function and survival...
February 2018: Peptides
Florentina Tofoleanu, Ye Yuan, Frank C Pickard, Bartlomiej Tywoniuk, Bernard R Brooks, Nicolae-Viorel Buchete
Human Islet Amyloid Polypeptide (hIAPP), also known as Amylin, is a 37-aminoacid peptide, co-secreted with insulin and widely found in fibril form in type-2 diabetes patients. By using all-atom molecular dynamics simulations, we study hIAPP fibril segments (i.e., protofilaments) formed with sequences of naturally-occurring variants from cat, rat and pig, presenting different aggregation propensities. We characterize the effect of mutations on the structural dynamics of solution-formed hIAPP protofilament models built from solid-state NMR data...
February 6, 2018: Journal of Physical Chemistry. B
Aimilia Lydia Kalafateli, Daniel Vallöf, Elisabet Jerlhag
Alcohol expresses its reinforcing properties by activating areas of the mesolimbic dopamine system, which consists of dopaminergic neurons projecting from the ventral tegmental area to the nucleus accumbens. The findings that reward induced by food and addictive drugs involve common mechanisms raise the possibility that gut-brain hormones, which control appetite, such as amylin, could be involved in reward regulation. Amylin decreases food intake, and despite its implication in the regulation of natural rewards, tenuous evidence support amylinergic mediation of artificial rewards, such as alcohol...
February 6, 2018: Addiction Biology
Yu Yuan, Yuan-Bo Li, Zheng-Fu Tai, Yi-Peng Xie, Xu-Feng Pu, Jian Gao
Pramlintide acetate (Symlin®), a synthetic analogue of the human hormone amylin. It was approved in March 2005 as a subcutaneous injection for the adjunctive treatment of patients who have type 1 or 2 diabetes mellitus. The objective of current investigation was to study the degradation behavior of pramlintide acetate under different ICH recommended stress conditions by HPLC and LC-MS. Pramlintide acetate was subjected to stress conditions of hydrolysis (acidic or alkaline), oxidation, photolysis and thermal decomposition...
January 2018: Journal of Food and Drug Analysis
Vladimir Kopysov, Mikhail V Gorshkov, Oleg V Boyarkin
We use 2D UV-MS cold-ion spectroscopy for the identification of l-Asp, d-Asp, l-isoAsp and d-isoAsp residues in a fragment peptide derived from the hormone protein amylin. Relative solution concentrations of all four isoforms in an equimolar quaternary mixture have been determined within 4% error. This method demonstrates that for binary mixtures of the peptides an accuracy of 2.5% can be reached in few-second measurements.
January 30, 2018: Analyst
Luiza C S Erthal, Luana Jotha-Mattos, Flávio Alves Lara, Sabrina Alves Dos Reis, Bernardo Miguel de Oliveira Pascarelli, Cinthia Melo Costa, Kleber L A Souza, Luís Maurício T R Lima
The human amylin is a pancreatic peptide hormone found in hyperhormonemic state along with insulin in subclinical diabetes. Amylin has been associated with the pathology of type 2 diabetes, particularly due to its ability to assembly into toxic oligomers and amyloid specimens. On the other hand, some variants such as murine amylin has been described as non-amyloidogenic, either in vitro or in vivo. Recent data have demonstrated the amyloid propensity of murine amylin and the therapeutic analogue pramlintide, suggesting a universality for amylin amyloidosis...
January 25, 2018: Molecular and Cellular Biochemistry
Jia-Jung Ho, Ayanjeet Ghosh, Tianqi O Zhang, Martin T Zanni
Two-dimensional sum-frequency generation spectroscopy (2D SFG) is used to study the structures of the pentapeptide FGAIL on hydrogen bond promoting surfaces. FGAIL is the most amyloidogenic portion of the human islet amyloid polypeptide (hIAPP or amylin). In the presence of a pure gold surface, FGAIL does not form ordered structures. When the gold is coated with a self-assembled monolayer of mercaptobenzoic acid (MBA), 2D SFG spectra reveal features associated with β-sheets. Also observed are cross peaks between the FGAIL peptides and the carboxylic acid groups of the MBA monolayer, indicating that the peptides are in close contact with the surface headgroups...
January 25, 2018: Journal of Physical Chemistry. A
Ivan Ferraz-Amaro, Raquel López-Mejias, Beatriz Tejera-Segura, Antonia M de Vera-González, Begoña Ubilla, Jose M Olmos, José Luis Hernández, Miguel Angel González-Gay
OBJECTIVES: Amylin, which is co-secreted with insulin, plays a role in glycemic regulation and is impaired in type 2 diabetes. In the present study we assess, for the first time, the implication of amylin in the development of insulin resistance (IR) in rheumatoid arthritis (RA). METHODS: This was a cross-sectional study involving 361 non-diabetic individuals, 151 patients with RA and 210 sex-matched controls. Insulin, C-peptide, amylin, lipoprotein serum concentrations, and IR indexes by homeostatic model assessment (HOMA2) were evaluated in patients and controls...
January 15, 2018: Clinical and Experimental Rheumatology
S Nurdiana, Y M Goh, A Hafandi, S M Dom, A Nur Syimal'ain, N M Noor Syaffinaz, M Ebrahimi
Despite the fact that Ficus deltoidea and vitexin played important roles in controlling hyperglycemia, an effective mitigation strategy dealing with cognitive deficit observed in diabetes, little is known about its neuroprotective effects. The study is aimed to determine changes in behavioral, gyrification patterns and brain oxidative stress markers in streptozotocin (STZ)-induced diabetic rats following F. deltoidea and vitexin treatments. Diabetic rats were treated orally with metformin, methanolic extract of F...
January 2018: Journal of Traditional and Complementary Medicine
H Suzuki, T Yamamoto
Immunohistochemical techniques were employed to investigate the distribution of amylin-like immunoreactive cells in the pancreas of gecko Homopholis fasciata. Four types of endocrine cells were distinguished: insulin immunoreactive (B cells), pancreatic polypeptide immunoreactive (PP cells), glucagon and pancreatic polypeptide immunoreactive (A/PP cells) and somatostatin immunoreactive cells (D cells). Pancreatic islets contained B, A/PP and D cells, whereas extrainsular regions contained B, D and PP cells...
January 8, 2018: Anatomia, Histologia, Embryologia
Kathrin Abegg, Andreas Hermann, Christina N Boyle, Sebastien G Bouret, Thomas A Lutz, Thomas Riediger
The area postrema (AP) and the nucleus of the solitary tract (NTS) are important hindbrain centers involved in the control of energy homeostasis. The AP mediates the anorectic action and the inhibitory effect on gastric emptying induced by the pancreatic hormone amylin. Amylin's target cells in the AP project to the NTS, an integrative relay center for enteroceptive signals. Perinatal hormonal and metabolic factors influence brain development. A postnatal surge of the adipocyte-derived hormone leptin represents a developmental signal for the maturation of projections between hypothalamic nuclei controlling energy balance...
2017: Frontiers in Endocrinology
Elizabeth G Mietlicki-Baase
Alzheimer's disease (AD) is a neurodegenerative disease for which we currently lack effective treatments or a cure. The pancreatic peptide hormone amylin has recently garnered interest as a potential pharmacological target for the treatment of AD. A number of studies have demonstrated that amylin and amylin analogs like the FDA-approved diabetes drug pramlintide can reduce amyloid burden in the brain and improve cognitive symptoms of AD. However, other data suggest that amylin may have pathological effects in AD due to its propensity to misfold and aggregate under certain conditions...
December 9, 2017: Neuropharmacology
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