68 results on '"Jessica S. Fortin"'
Search Results
2. Understanding alpha-synuclein aggregation propensity in animals and humans
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Natalie G. Horgan, Annie M. McCarty, Ashley A. Hetak, Hailey B. Penticoff, and Jessica S. Fortin
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Aggregation ,Alpha-synuclein ,Fibril ,Parkinson's disease ,Thioflavin T (ThT) ,Transmission electron microscopy (TEM) ,Biology (General) ,QH301-705.5 ,Biochemistry ,QD415-436 - Abstract
Alpha-synuclein (α-syn) aggregation plays a critical role in the pathogenicity of Parkinson's Disease (PD). This study aims to evaluate the aggregation propensity of α-syn fragment peptides designed using the variability found in humans and animals. Thioflavin T (ThT) and transmission electron microscopy (TEM) were used to validate the formation of fibrils to identify important amino acid residues. Human α-syn fragments 51–75, 37–61, 62–86, 76–100, and 116–140 demonstrate a significantly higher tendency to aggregate compared to fragments 1–25, 26–50, and 91–115. All species analyzed of the α-syn 37–61 and 62–86 regions were shown to form fibrils on both ThT and TEM. The α-syn 37–61 and 62–86 fragment regions exhibited a high susceptibility to aggregation, with fibril formation observed in all species. The A53T mutation in several α-syn 37–61 fragments may enhance their propensity for aggregation, suggesting a correlation between this mutation and the capacity for fibril formation. Furthermore, the presence of the non-amyloid-β component (NAC) region, specifically in α-syn 62–86, was consistently observed in several fragments that displayed fibril formation, indicating a potential correlation between the NAC region and the process of fibril formation in α-syn. Finally, the combination of a high quantity of valine and a low quantity of acidic amino acids in these fragments may serve as indicators of α-syn fibril formation.
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- 2024
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3. 1,4-Diurea- and 1,4-Dithiourea-Substituted Aromatic Derivatives Selectively Inhibit α‑Synuclein Oligomer Formation In Vitro
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Susantha K. Ganegamage, Eduardo Ramirez, Heba Alnakhala, Arati Tripathi, Cuong Calvin Duc Nguyen, Ashique Zami, Raluca Ostafe, Shiliang Tian, Ulf Dettmer, and Jessica S. Fortin
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Chemistry ,QD1-999 - Published
- 2023
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4. Investigation of serum amyloid a within animal species focusing on the 1-25 amino acid region
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Natalie G. Horgan, Kendall B. E. Moore, and Jessica S. Fortin
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Animals ,aggregation ,amyloid-like fibrils ,oligomers ,serum amyloid A1 ,zoology ,Veterinary medicine ,SF600-1100 - Abstract
AbstractAA amyloidosis, characterized by the misfolding of serum amyloid A (SAA) protein, is the most common amyloid protein disorder across multiple species. SAA is a positive-acute phase protein synthesized by the liver in response to inflammation or stress, and it normally associates with high-density lipoprotein at its N-terminus. In this study, we focused on the 1-25 amino acid (aa) region of the complete 104 aa SAA sequence to examine the aggregation propensity of AA amyloid. A library comprising eight peptides from different species was assembled for analysis. To access the aggregation propensity of each peptide region, a bioinformatic study was conducted using the algorithm TANGO. Congo red (CR) binding assays, Thioflavin T (ThT) assays, and transmission electron microscopy (TEM) were utilized to evaluate whether the synthesized peptides formed amyloid-like fibrils. All synthetic SAA 1-25 congeners resulted in amyloid-like fibrils formation (per CR and/or ThT staining and TEM detection) at the exception of the ferret SAA1-25 fragment, which generated plaque-like materials by TEM. Ten residues were preserved among SAA 1-25 congeners resulting in amyloid-like fibrils, i.e. F6, E9, A10, G13, D16, M17, A20, Y21, D23, and M24. Amino acid residues highlighted by this study may have a role in increasing the propensity for amyloid-like fibril formation. This study put an emphasis on region 1-25 in the mechanism of SAA1 misfolding.
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- 2023
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5. Diabetes mellitus drug discovery: insights into targeting feline and human amylin with small molecules
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Kendall B. E. Moore, Natalie G. Horgan, Brooke Lenters, and Jessica S. Fortin
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Amylin ,cat ,drug discovery ,islet amyloid polypeptide ,pancreatic amyloidosis ,type 2 diabetes ,Veterinary medicine ,SF600-1100 - Abstract
AbstractBackground Type 2 diabetes (T2D) is a health concern for both humans and cats, with cases rising over the past decade. Around 70% of patients from either species exhibit pancreatic aggregates of islet amyloid polypeptide (IAPP), a protein that proves toxic upon misfolding. These misfolded protein aggregates congregate in the islets of Langerhans of the pancreas, diminishing the capability of β-cells to produce insulin and further perpetuating disease.Objective Our team’s drug discovery program is investigating newly synthesized compounds that could diminish aggregates of both human and feline IAPP, potentially disrupting the progression of T2D.Material and methods We prepared 24 compounds derived from diaryl urea, as ureas have previously demonstrated great potential at reducing accumulations of misfolded proteins. Biophysical methods were employed to analyze the anti-aggregation activity of these compounds at inhibiting and/or disrupting IAPP fibril formation in vitro.Results The results demonstrate that compounds 12 and 24 were most effective at reducing the fibrillization and aggregation of both human and feline IAPP. When compared with the control for each experiment, samples treated with either compound 12 or 24 exhibited fewer accumulations of amyloid-like fibrils.Conclusion Urea-based compounds, such as compounds 12 and 24, may prove crucial in future pre-clinical studies in the search for therapeutics for T2D.
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- 2023
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6. Discovery of 4-aminoindole carboxamide derivatives to curtail alpha-synuclein and tau isoform 2N4R oligomer formation
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Eduardo Ramirez, Sehong Min, Susantha K. Ganegamage, Kazuma Shimanaka, Magaly Guzman Sosa, Ulf Dettmer, Jean-Christophe Rochet, and Jessica S. Fortin
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Alzheimer’s disease ,Amide ,Alpha-synuclein ,Fibril ,Oligomer ,Tau isoform 2N4R ,Chemistry ,QD1-999 - Abstract
Alzheimer’s disease (AD) is a multifactorial, chronic neurodegenerative disease characterized by the presence of extracellular β-amyloid (Aβ) plaques, intraneuronal neurofibrillary tangles (NFTs), activated microglial cells, and an inflammatory state (involving reactive oxygen species production) in the brain. NFTs are comprised of misfolded and hyperphosphorylated forms of the microtubule-binding protein tau. Interestingly, the trimeric form of the 2N4R splice isoform of tau has been found to be more toxic than the trimeric 1N4R isoform in neuron precursor cells. Few drug discovery programs have focused on specific tau isoforms. The present drug discovery project is centered on the anti-aggregation effect of a series of seventeen 4- or 5-aminoindole carboxamides on the 2N4R isoform of tau. The selection of the best compounds was performed using α-synuclein (α-syn). The anti-oligomer and -fibril activities of newly synthesized aminoindole carboxamide derivatives were evaluated with biophysical methods, such as thioflavin T fluorescence assays, photo-induced cross-linking of unmodified proteins, and transmission electron microscopy. To evaluate the reduction of inclusions and cytoprotective effects, M17D neuroblastoma cells expressing inclusion-forming α-syn were treated with the best amide representatives. The 4-aminoindole carboxamide derivatives exhibited a better anti-fibrillar activity compared to their 5-aminoindole counterparts. The amide derivatives 2, 8, and 17 exerted anti-oligomer and anti-fibril activities on α-syn and the 2N4R isoform of tau. At a concentration of 40 µM, compound 8 reduced inclusion formation in M17D neuroblastoma cells expressing inclusion-prone αSynuclein3K::YFP. Our results demonstrate the potential of 4-aminoindole carboxamide derivatives with regard to inhibiting the oligomer formation of α-syn and tau (2N4R isoform) for further optimization prior to pre-clinical studies.
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- 2023
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7. Equine pituitary pars intermedia dysfunction: a spontaneous model of synucleinopathy
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Jessica S. Fortin, Ashley A. Hetak, Kelsey E. Duggan, Caroline M. Burglass, Hailey B. Penticoff, and Harold C. Schott
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Medicine ,Science - Abstract
Abstract Equine pituitary pars intermedia dysfunction (PPID) is a common endocrine disease of aged horses that shows a similar pathophysiology as Parkinson’s Disease (PD) with increased levels of α-synuclein (α-syn). While α-syn is thought to play a pathogenic role in horses with PPID, it is unclear if α-syn is also misfolded in the pars intermedia and could similarly promote self-aggregation and propagation. Consequently, α-syn was isolated from the pars intermedia from groups of healthy young and aged horses, and aged PPID-afflicted horses. Seeding experiments confirmed the prion-like properties of α-syn isolated from PPID-afflicted horses. Next, detection of α-syn fibrils in pars intermedia via transmission electron microscopy (TEM) was exclusive to PPID-afflicted horses. A bank of fragment peptides was designed to further characterize equine α-syn misfolding. Region 62–87 of equine and human α-syn peptides was found to be most prone to aggregation according to Tango bioinformatic program and kinetics of aggregation via a thioflavin T fluorescence assay. In both species, fragment peptide 62–87 is capable of generating mature fibrils as demonstrated by TEM. The combined animal, bioinformatic, and biophysical studies provide evidence that equine α-syn is misfolded in PPID horses.
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- 2021
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8. Revisiting misfolding propensity of serum amyloid A1: Special focus on the signal peptide region
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Morgan S. Haines, Eduardo Ramirez, Kendall B.E. Moore, and Jessica S. Fortin
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Amyloid A ,Fibril assembly ,Protein misfolding ,Serum amyloid A ,Signal peptide ,Systemic amyloidosis ,Biology (General) ,QH301-705.5 ,Biochemistry ,QD415-436 - Abstract
AA amyloidosis is the result of overproduction and aberrant processing of acute-phase serum amyloid A1 (SAA1) by hepatocytes. Proteolytic cleavage of SAA1 is believed to play a central role in AA amyloid formation. The SAA1 protein undergoes a cleavage of 18 residues consisting of the signal peptide at the N-terminal region. To better understand the mechanism behind systemic amyloidosis in the SAA1 protein, we studied the misfolding propensity of the signal peptide region. We first examined the signal peptide amino acid SAA derived from different animal species. A library of 16 peptides was designed to evaluate the propensity of aggregation. The amyloidogenic potential of each SAA1 signal peptide homolog was assessed using in silico Tango program, thioflavin T (ThT) fluorescence, transmission electron microscopy (TEM), and seeding with misfolded human SAA1 signal peptide. After 7 days of incubation, most of the SAA1 signal peptide fragments had the propensity to form fibrils at a concentration of 100 μM in 50 mM Tris buffer at 37 °C by TEM. All peptides were able to generate fibrils at a higher concentration, i.e 500 μM in 25 mM Tris buffer with 50% HFIP, by ThT. All SAA1 signal synthetic peptides designed from the different animal species had the propensity to misfold and form fibrils, particularly in species with low occurrence of systemic amyloidosis. The human SAA1 signal peptide region was capable to seed the SAA1 1–25 and 32–47 peptide regions. Characterizing fibrillar conformations are relevant for seeding intact and/or fragmented SAA, which may contribute, to the mechanism of protein misfolding. This research signifies the importance of the signal peptide region and its possible contribution to the misfolding of aggregation-prone proteins.
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- 2022
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9. Widespread severe myodegeneration in a compound heterozygote female dog with dystrophin deficiency
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Jessica S. Fortin, Chady H. Hakim, Scott Korte, N. Nora Yang, Scott D. Fitzgerald, Gayle C. Johnson, Bruce F. Smith, and Dongsheng Duan
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canine ,compound heterozygote ,Duchenne muscular dystrophy ,dystrophin ,Veterinary medicine ,SF600-1100 - Abstract
Abstract The University of Missouri (MU) has established a colony of dystrophin‐deficient dogs with a mixed breed background to mirror the variable pathologic effects of dystrophinopathies between persons of a given kindred to further the understanding of the genetic and molecular basis of the variable phenotype; thus to facilitate discovery of an effective therapeutic strategy. Herein we report the phenotype and genotype of a normal‐appearing 10‐month‐old colony female that died suddenly. At necropsy examination, there were reduced skeletal and laryngeal muscle volume and mild dilatation of the oesophagus. Microscopic findings consisted of extensive degeneration and regeneration of the axial skeletal, tongue, oesophageal, and laryngeal muscles that were characterized by considerable central nucleation, individual fibre mineralization and interstitial fibrosis. The myocardial findings were limited to infiltration of adipose cells in the interstitium. The female dog was a compound heterozygote with one X chromosome carrying a point mutation in intron 6 of the dystrophin gene and the other X chromosome carrying a repetitive element insertion in intron 13 of the dystrophin gene. Although the direct cause of death was uncertain, it might likely be due to sudden cardiac death as has been seen in Duchenne muscular dystrophy patients. This case demonstrated dystrophinopathy in female dogs that have no ameliorating normal X chromosome.
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- 2021
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10. Nephroblastoma in a Sprague Dawley rat unrelated to titanium dioxide nanoparticle exposure in utero
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Samantha J. Glaspell, Katie J. Knapek, Ida M. Washington, Scott D. Fitzgerald, and Jessica S. Fortin
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metastasis ,nephroblastoma ,rodent ,TiO2 ,Wilms' tumour ,Veterinary medicine ,SF600-1100 - Abstract
Abstract Nephroblastoma is an embryonal tumour that has rarely been reported in laboratory rats. In this case report, a large nephroblastoma with peritoneal seeding was found during necropsy in an 11‐month‐old, female, Sprague Dawley rat. The rat had a history of indirect exposure to nano‐TiO2 (titanium dioxide nanoparticles) during maternal gestation. A firm mass in the upper right abdominal quadrant was palpated. Four weeks later, the animal quickly declined. Nephroblastoma was confirmed by histopathology. Only one rat developed nephroblastoma among the ten littermates. Nephroblastomas in Sprague Dawley rats are typically spontaneous tumours with non‐malignant mesenchymal elements. The capability to induce a nephroblastoma with nano‐TiO2 is less likely in this case.
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- 2021
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11. Restoring pars intermedia dopamine concentrations and tyrosine hydroxylase expression levels with pergolide: evidence from horses with pituitary pars intermedia dysfunction
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Jessica S. Fortin, Matthew J. Benskey, Keith J. Lookingland, Jon S. Patterson, Erin B. Howey, John L. Goudreau, and Harold C. Schott
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Dopamine agonist ,Equine ,Parkinson disease animal model ,Pituitary pars intermedia adenoma ,Veterinary medicine ,SF600-1100 - Abstract
Abstract Background Pituitary pars intermedia dysfunction (PPID) develops slowly in aged horses as degeneration of hypothalamic dopaminergic neurons leads to proliferation of pars intermedia (PI) melanotropes through hyperplasia and adenoma formation. Dopamine (DA) concentrations and tyrosine hydroxylase (TH) immunoreactivity are markedly reduced in PI tissue of PPID-affected equids and treatment with the DA receptor agonist pergolide results in notable clinical improvement. Thus, we hypothesized that pergolide treatment of PPID-affected horses would result in greater DA and TH levels in PI tissue collected from PPID-affected horses versus untreated PPID-affected horses. To test this hypothesis, pituitary glands were removed from 18 horses: four untreated PPID-affected horses, four aged and four young horses without signs of PPID, and six PPID-affected horses that had been treated with pergolide at 2 µg/kg orally once daily for 6 months. DA concentrations and TH expression levels in PI tissues were determined by high performance liquid chromatography with electrochemical detection and Western blot analyses, respectively. Results DA and TH levels were lowest in PI collected from untreated PPID-affected horses while levels in the pergolide treated horses were similar to those of aged horses without signs of PPID. Conclusions These findings provide evidence of restoration of DA and TH levels following treatment with pergolide. Equine PPID is a potential animal model of dopaminergic neurodegeneration, which could provide insight into human neurodegenerative diseases.
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- 2020
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12. 5-Nitro-1,2-benzothiazol-3-amine and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide Modulate α-Synuclein and Tau Aggregation
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Eduardo Ramirez, Susantha K. Ganegamage, Ahmed A. Elbatrawy, Heba Alnakhala, Kazuma Shimanaka, Arati Tripathi, Sehong Min, Jean-Christophe Rochet, Ulf Dettmer, and Jessica S. Fortin
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General Chemical Engineering ,General Chemistry - Published
- 2023
13. Anti-fibrillization effects of sulfonamide derivatives on
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Jessica S, Fortin, Kazuma, Shimanaka, A Prasanth, Saraswati, Mengyu, Liu, Kuang-Wei, Wang, Hsiao-Tien, Hagar, Soham, Maity, Susantha K, Ganegamage, Edmund, Ellsworth, Scott E, Counts, Babak, Borhan, Ulf, Dettmer, and Min-Hao, Kuo
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Article - Abstract
In contrast to Aβ plaques, the spatiotemporal distribution of neurofibrillary tangles of hyperphosphorylated tau (p-tau) predicts cognitive impairment in Alzheimer’s disease (AD), underscoring the key pathological role of p-tau and the utmost need to develop AD therapeutics centering upon the control of p-tau aggregation and cytotoxicity. Our drug discovery program is focused on compounds that prevent the aggregation and cytotoxicity of p-tau moieties of the tau isoform 1N4R due to its prevalence (1 N) and long-distance trans-synaptic propagation (4R). We prepared and tested twenty-four newly synthesized small molecules representing the urea (1, 2, 3), sulfonylurea (4), and sulfonamide (5–24) series and evaluated their anti-aggregation effects with biophysical methods (thioflavin T and S fluorescence assays, transmission electron microscopy) and intracellular inclusion cell-based assays. Pre-evaluation was performed on alpha-synuclein (α-syn) to identify molecules to be challenged with p-tau. The sulfonamide derivatives 18 and 20 exhibited an anti-fribrillization activity on α-syn and p-tau. Sulfonamide compounds 18 and 20 reduced inclusion formation in M17D neuroblastoma cells that express inclusion-prone αSynuclein3K::YFP. This project advances new concepts in targeting prone-to-aggregate proteins such as α-syn and p-tau, and provides a molecular scaffold for further optimization and pre-clinical studies focused on AD drug development.
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- 2022
14. Structure-activity relationships of small molecule inhibitors of feline and human islet amyloid polypeptide fibril formation
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Jessica S Fortin, Brooke Lenters, and Eduardo Ramirez
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- 2022
15. Survey of amyloidosis cases among different free-living wild and zoo animals
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Hailey B. Penticoff, Ashley A. Hetak, Dalen W. Agnew, Jessica S. Fortin, and Hannah K Hipkiss
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Amyloid ,Serum Amyloid A Protein ,2019-20 coronavirus outbreak ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Amyloidosis ,Amyloidogenic Proteins ,030204 cardiovascular system & hematology ,Biology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,AA amyloidosis ,Immunology ,Internal Medicine ,medicine ,Preventive intervention ,Animals ,Humans ,Animals, Zoo ,Serum amyloid A ,030217 neurology & neurosurgery - Abstract
Amyloidosis comprises a range of protein-folding disorders characterised by a buildup of amyloid deposits in one or multiple organs. The pathogenesis and pathologic findings of amyloidosis can vary widely due to the nature of the precursor protein. In veterinary medicine, there are 10 proteins known to form amyloid deposits in various organs. This review aims to compare amyloidosis cases among different free-living wild and zoo animals focussing in part on the determination of the species particularly susceptible to the amyloid formation and specific prone-to-aggregate protein commonly involved. This review addresses the transmission of AA amyloidosis pertinent to institutions, such as zoos, housing multiple individuals and species in relatively close proximity. In addition, this review includes summarisation for definitive diagnosis of single or multiple cases of amyloidosis affecting free-living wild and zoo animals. Insights into the diversity, transmission, and pathogenesis of known amyloidogenic proteins and species prevalently affected may help to establish a preventive intervention and stimulate the discovery of new diagnostic and therapeutic strategies.
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- 2021
16. Revisiting Small Molecule Inhibitors of Amyloid‐β Aggregation
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Kendall B. E. Moore, James P. T. Pirela, and Jessica S. Fortin
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Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
17. A Phenotypic‐based Drug Discovery Approach to Inhibit the Misfolding of Hyperphosphorylated Tau Isoform 1N4R
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Jessica S. Fortin, Kuang‐Wei Wang, Hsiao T. Chien, and Min‐Hao Kuo
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Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
18. Understanding Alpha‐synuclein Aggregation Propensity with a Fragment Peptide Library
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Jessica S. Fortin, Annie M. McCarty, Hailey B. Penticoff, and Ashley A. Hetak
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Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
19. Misfolding Propensity of SAA1 Fragments: Special Focus on the Signal Peptide Region
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Morgan S. Haines, James P. Pirela, Kendra N. Nylen, and Jessica S. Fortin
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Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
20. Widespread severe myodegeneration in a compound heterozygote female dog with dystrophin deficiency
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Bruce F. Smith, Scott D. Fitzgerald, Chady H. Hakim, Dongsheng Duan, Scott W. Korte, Jessica S. Fortin, N. Nora Yang, and Gayle C. Johnson
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Duchenne muscular dystrophy ,Heterozygote ,Pathology ,medicine.medical_specialty ,Veterinary medicine ,canine ,Adipose tissue ,Case Report ,Case Reports ,Compound heterozygosity ,dystrophin ,Muscular Dystrophies ,Sudden cardiac death ,Dogs ,Fatal Outcome ,SF600-1100 ,Genotype ,medicine ,Animals ,Dog Diseases ,X chromosome ,General Veterinary ,biology ,business.industry ,compound heterozygote ,medicine.disease ,Laryngeal Muscle ,biology.protein ,Female ,Dystrophin ,business - Abstract
The University of Missouri (MU) has established a colony of dystrophin‐deficient dogs with a mixed breed background to mirror the variable pathologic effects of dystrophinopathies between persons of a given kindred to further the understanding of the genetic and molecular basis of the variable phenotype; thus to facilitate discovery of an effective therapeutic strategy. Herein we report the phenotype and genotype of a normal‐appearing 10‐month‐old colony female that died suddenly. At necropsy examination, there were reduced skeletal and laryngeal muscle volume and mild dilatation of the oesophagus. Microscopic findings consisted of extensive degeneration and regeneration of the axial skeletal, tongue, oesophageal, and laryngeal muscles that were characterized by considerable central nucleation, individual fibre mineralization and interstitial fibrosis. The myocardial findings were limited to infiltration of adipose cells in the interstitium. The female dog was a compound heterozygote with one X chromosome carrying a point mutation in intron 6 of the dystrophin gene and the other X chromosome carrying a repetitive element insertion in intron 13 of the dystrophin gene. Although the direct cause of death was uncertain, it might likely be due to sudden cardiac death as has been seen in Duchenne muscular dystrophy patients. This case demonstrated dystrophinopathy in female dogs that have no ameliorating normal X chromosome., A 10‐month‐old mixed breed female dog in a muscular dystrophy research colony at the University of Missouri died suddenly without premonitory symptoms. At necropsy examination, there were reduced skeletal and laryngeal muscle volume and mild dilatation of the esophagus. Microscopic findings consisted of extensive degeneration and regeneration of the axial skeletal, tongue, esophageal, and laryngeal muscles that were characterized by considerable central nucleation, individual fiber mineralization and interstitial fibrosis.
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- 2021
21. Hyperphosphorylated tau (p-tau) and drug discovery in the context of Alzheimer's disease and related tauopathies
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Kendall B.E. Moore, Ta-Jung Hung, and Jessica S. Fortin
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Pharmacology ,Drug Discovery - Published
- 2023
22. Impact of Preanalytical Factors During Histology Processing on Section Suitability for Digital Image Analysis
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Karen Copeland, Elizabeth A Chlipala, Brad Bolon, Mark Butters, Miles Brous, Roni Archuletta, and Jessica S. Fortin
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040301 veterinary sciences ,Computer science ,H&E stain ,Toxicology ,histology process validation ,Pathology and Forensic Medicine ,0403 veterinary science ,Mice ,03 medical and health sciences ,Digital image ,0302 clinical medicine ,image analysis ,Protocol design ,Biomarkers, Tumor ,Image Processing, Computer-Assisted ,Animals ,reproducibility ,Molecular Biology ,Digital pathology ,Histology ,Original Articles ,04 agricultural and veterinary sciences ,Cell Biology ,Immunohistochemistry ,preanalytical factors ,Staining ,030220 oncology & carcinogenesis ,Digital image analysis ,precision ,Tissue staining ,digital pathology ,Algorithms ,Software ,Biomedical engineering - Abstract
Digital image analysis (DIA) is impacted by the quality of tissue staining. This study examined the influence of preanalytical variables—staining protocol design, reagent quality, section attributes, and instrumentation—on the performance of automated DIA software. Our hypotheses were that (1) staining intensity is impacted by subtle differences in protocol design, reagent quality, and section composition and that (2) identically programmed and loaded stainers will produce equivalent immunohistochemical (IHC) staining. We tested these propositions by using 1 hematoxylin and eosin stainer to process 13 formalin-fixed, paraffin-embedded (FFPE) mouse tissues and by using 3 identically programmed and loaded immunostainers to process 5 FFPE mouse tissues for 4 cell biomarkers. Digital images of stained sections acquired with a commercial whole slide scanner were analyzed by customizable algorithms incorporated into commercially available DIA software. Staining intensity as viewed qualitatively by an observer and/or quantitatively by DIA was affected by staining conditions and tissue attributes. Intrarun and inter-run IHC staining intensities were equivalent for each tissue when processed on a given stainer but varied measurably across stainers. Our data indicate that staining quality must be monitored for each method and stainer to ensure that preanalytical factors do not impact digital pathology data quality.
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- 2020
23. Restoring pars intermedia dopamine concentrations and tyrosine hydroxylase expression levels with pergolide: evidence from horses with pituitary pars intermedia dysfunction
- Author
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John L. Goudreau, Jessica S. Fortin, Jon S. Patterson, Erin B. Howey, Matthew J. Benskey, Harold C. Schott, and Keith J. Lookingland
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Agonist ,Aging ,medicine.medical_specialty ,Tyrosine 3-Monooxygenase ,040301 veterinary sciences ,medicine.drug_class ,Dopamine ,Pituitary Diseases ,Pituitary pars intermedia adenoma ,Dopamine agonist ,0403 veterinary science ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Parkinson disease animal model ,Pituitary pars intermedia dysfunction ,Animals ,Medicine ,Horses ,Pituitary Gland, Intermediate ,Pergolide ,lcsh:Veterinary medicine ,General Veterinary ,Tyrosine hydroxylase ,business.industry ,Equine ,Dopaminergic ,Pars intermedia ,04 agricultural and veterinary sciences ,General Medicine ,Endocrinology ,Dopamine Agonists ,lcsh:SF600-1100 ,Horse Diseases ,business ,030217 neurology & neurosurgery ,Research Article ,medicine.drug - Abstract
Background Pituitary pars intermedia dysfunction (PPID) develops slowly in aged horses as degeneration of hypothalamic dopaminergic neurons leads to proliferation of pars intermedia (PI) melanotropes through hyperplasia and adenoma formation. Dopamine (DA) concentrations and tyrosine hydroxylase (TH) immunoreactivity are markedly reduced in PI tissue of PPID-affected equids and treatment with the DA receptor agonist pergolide results in notable clinical improvement. Thus, we hypothesized that pergolide treatment of PPID-affected horses would result in greater DA and TH levels in PI tissue collected from PPID-affected horses versus untreated PPID-affected horses. To test this hypothesis, pituitary glands were removed from 18 horses: four untreated PPID-affected horses, four aged and four young horses without signs of PPID, and six PPID-affected horses that had been treated with pergolide at 2 µg/kg orally once daily for 6 months. DA concentrations and TH expression levels in PI tissues were determined by high performance liquid chromatography with electrochemical detection and Western blot analyses, respectively. Results DA and TH levels were lowest in PI collected from untreated PPID-affected horses while levels in the pergolide treated horses were similar to those of aged horses without signs of PPID. Conclusions These findings provide evidence of restoration of DA and TH levels following treatment with pergolide. Equine PPID is a potential animal model of dopaminergic neurodegeneration, which could provide insight into human neurodegenerative diseases.
- Published
- 2020
24. Pathology in Practice
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Ji-Hang Yin and Jessica S. Fortin
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Male ,General Veterinary ,Cats ,Animals ,Cat Diseases ,Histoplasmosis - Published
- 2020
25. Recent Advances in the Discovery of Therapeutics to Curtail Islet Amyloid Polypeptide Aggregation for Type 2 Diabetes Treatment (Adv. Biology 10/2022)
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Alyssa A. Smith, Kendall B. E. Moore, Patrick M. Ambs, Akella Prasanth Saraswati, and Jessica S. Fortin
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Biomaterials ,Biomedical Engineering ,General Biochemistry, Genetics and Molecular Biology - Published
- 2022
26. Characterization of G‐quadruplex Structures in Serum Amyloid A Gene as a Novel Approach for Systemic Amyloidosis Therapy
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Hailey B. Penticoff and Jessica S. Fortin
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Chemistry ,Genetics ,Cancer research ,Serum amyloid A ,G-quadruplex ,Molecular Biology ,Biochemistry ,Systemic amyloidosis ,Gene ,Biotechnology - Published
- 2021
27. Small Molecule Inhibitors of Hyperphosphorylated Tau Aggregation and Cytotoxicity
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Min Hao Kuo, Kuang‐Wei Wang, Jessica S. Fortin, and Mengyu Liu
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Chemistry ,Genetics ,Biophysics ,Cytotoxicity ,Molecular Biology ,Biochemistry ,Small molecule ,Biotechnology - Published
- 2021
28. Small Molecule Targeting of Feline Islet Amyloid Polypeptide for the Management of Feline Diabetes Mellitus
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Anisa M. Rashid, Thomas B. Thompson, Malikah O’Dell, Nurhanis B.M. Isa, Kelsey E. Duggan, and Jessica S. Fortin
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geography ,geography.geographical_feature_category ,Amyloid ,business.industry ,medicine.disease ,Islet ,Biochemistry ,Small molecule ,Diabetes mellitus ,Genetics ,medicine ,Cancer research ,business ,Molecular Biology ,Biotechnology - Published
- 2021
29. Potential Neuroprotection for Equine Pituitary Pars Intermedia Dysfunction
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Jessica S. Fortin and Ashley A. Hetak
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medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,Genetics ,Pituitary pars intermedia dysfunction ,Medicine ,business ,Molecular Biology ,Biochemistry ,Neuroprotection ,Biotechnology - Published
- 2021
30. Aggregation Propensity of Serum Amyloid A1 in Captive Zoo and Free‐living Wild Animals
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Hannah K Hipkiss and Jessica S. Fortin
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medicine.medical_specialty ,Endocrinology ,Internal medicine ,Genetics ,Serum amyloid A1 ,medicine ,Biology ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2021
31. In Silico and In Vitro Validation of Equine Alpha‐synuclein Misfolding Relevant to Pituitary Pars Intermedia Dysfunction
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Ashley A. Hetak, Kelsey E. Duggan, Hailey B. Penticoff, and Jessica S. Fortin
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Alpha-synuclein ,chemistry.chemical_compound ,chemistry ,In silico ,Genetics ,Pituitary pars intermedia dysfunction ,Biology ,Molecular Biology ,Biochemistry ,Molecular biology ,In vitro ,Biotechnology - Published
- 2021
32. Equine pituitary pars intermedia dysfunction: a spontaneous model of synucleinopathy
- Author
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Ashley A. Hetak, Caroline M. Burglass, Harold C. Schott, Hailey B. Penticoff, Kelsey E. Duggan, and Jessica S. Fortin
- Subjects
medicine.medical_specialty ,Aging ,Parkinson's disease ,Synucleinopathies ,Pituitary diseases ,Science ,animal diseases ,Biology ,Protein aggregation ,Fibril ,Article ,chemistry.chemical_compound ,Internal medicine ,medicine ,Pituitary pars intermedia dysfunction ,Animals ,Horses ,Pituitary Gland, Intermediate ,Multidisciplinary ,Endocrine disease ,Pars intermedia ,medicine.disease ,Pathophysiology ,nervous system diseases ,Disease Models, Animal ,Endocrinology ,chemistry ,nervous system ,alpha-Synuclein ,Medicine ,Thioflavin ,Horse Diseases ,Transmission electron microscopy - Abstract
Equine pituitary pars intermedia dysfunction (PPID) is a common endocrine disease of aged horses that shows a similar pathophysiology as Parkinson’s Disease (PD) with increased levels of α-synuclein (α-syn). While α-syn is thought to play a pathogenic role in horses with PPID, it is unclear if α-syn is also misfolded in the pars intermedia and could similarly promote self-aggregation and propagation. Consequently, α-syn was isolated from the pars intermedia from groups of healthy young and aged horses, and aged PPID-afflicted horses. Seeding experiments confirmed the prion-like properties of α-syn isolated from PPID-afflicted horses. Next, detection of α-syn fibrils in pars intermedia via transmission electron microscopy (TEM) was exclusive to PPID-afflicted horses. A bank of fragment peptides was designed to further characterize equine α-syn misfolding. Region 62–87 of equine and human α-syn peptides was found to be most prone to aggregation according to Tango bioinformatic program and kinetics of aggregation via a thioflavin T fluorescence assay. In both species, fragment peptide 62–87 is capable of generating mature fibrils as demonstrated by TEM. The combined animal, bioinformatic, and biophysical studies provide evidence that equine α-syn is misfolded in PPID horses.
- Published
- 2021
33. Author response for 'Widespread severe myodegeneration in a compound heterozygote female dog with dystrophin deficiency'
- Author
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Scott W. Korte, N. Nora Yang, Bruce F. Smith, Scott D. Fitzgerald, Gayle C. Johnson, Chady H. Hakim, Dongsheng Duan, and Jessica S. Fortin
- Subjects
medicine.medical_specialty ,Endocrinology ,biology ,business.industry ,Internal medicine ,Female dog ,medicine ,biology.protein ,Compound heterozygosity ,Dystrophin ,business - Published
- 2020
34. Author response for 'Nephroblastoma in a Sprague Dawley rat unrelated to titanium dioxide nanoparticle exposure in utero'
- Author
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Jessica S. Fortin, Katie J. Knapek, Samantha J. Glaspell, Scott D. Fitzgerald, and Ida M Washington
- Subjects
Sprague dawley ,medicine.medical_specialty ,chemistry.chemical_compound ,Endocrinology ,Chemistry ,In utero ,Internal medicine ,Titanium dioxide ,medicine ,Nanoparticle - Published
- 2020
35. In vitro characterization of urea derivatives to inhibit alpha-synuclein early-stage aggregation
- Author
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Nurhanis B.M. Isa, Rachel S. Kepczynski, Soham Maity, Kazuma Shimanaka, Babak Borhan, Ulf Dettmer, Jessica S. Fortin, Anisa M. Rashid, Laken N. Rivet, and Malikah O’Dell
- Subjects
Alpha-synuclein ,Chemistry ,Cytoplasmic inclusion ,Amyloidosis ,Organic Chemistry ,Resveratrol ,medicine.disease ,In vitro ,Analytical Chemistry ,Inorganic Chemistry ,chemistry.chemical_compound ,Biochemistry ,Polyphenol ,medicine ,Urea ,Cytotoxicity ,Spectroscopy - Abstract
Amyloidosis, a group of diseases caused by the fibrillation of prone-to-aggregate proteins, remains one of the most difficult ailments to treat human medicine. This study focuses on the amyloid protein, alpha-synuclein (α-syn), the major pathogenetic contributor to well-known diseases such as Parkinson's Disease (PD) and multiple system atrophy (MSA). We examine the effectiveness of our novel family of molecules, diaryl derivatives of urea, on the inhibition of early- and late-stage α-syn aggregation. Screening with Thioflavin-T (ThT) fluorescence assay has identified one compound 12 as a promising inhibitor for fibril formation (late-stage aggregation). Utilizing the Photo-induced Cross-linking of Unmodified Proteins (PICUP) assays, compound 12 impeded α-syn oligomerization (early-stage aggregation). In contrast to resveratrol, a polyphenol used as positive control, compound 12 delayed the lag time and did not generate globular structures of 5 nm per transmission electron microscopy (TEM). EC50 of compound 12 is 27.6 ± 1.3 µM. Compound 12 reduced cell inclusions and cytotoxicity in a dose-dependent manner using the inclusion-forming neuroblastoma cell-based assays. This family of compound has the potential to become an invaluable tool to abrogate, at the early-stage, α-syn aggregation.
- Published
- 2022
36. Hyperphosphorylation Renders Tau Prone to Aggregate and to Cause Cell Death
- Author
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Min Hao Kuo, Mengyu Liu, Hsin Lian Lin, Hye Kyong Kweon, Daniela Jimenez-Harrison, Yeou Guang Tsay, Nora Sheen Kuo, Xiexiong Deng, Stacy Hovde, Hsiao Tien Chien, Christopher A. Ayoub, Roland P.S. Kwok, Kuang Wei Wang, Thomas S. Dexheimer, Jeff Kuret, Philip C. Andrews, Daniel A. Bochar, Dexin Sui, and Jessica S. Fortin
- Subjects
0301 basic medicine ,Programmed cell death ,Cell Survival ,Neuroscience (miscellaneous) ,Hyperphosphorylation ,tau Proteins ,Neuropathology ,Biophysical Phenomena ,Article ,Cell Line ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Protein Aggregates ,0302 clinical medicine ,Superoxides ,mental disorders ,medicine ,Humans ,Protein Isoforms ,Phosphorylation ,chemistry.chemical_classification ,Reactive oxygen species ,Glycogen Synthase Kinase 3 beta ,Cell Death ,Neurofibrillary tangle ,medicine.disease ,Recombinant Proteins ,Cell biology ,Mitochondria ,030104 developmental biology ,Neurology ,chemistry ,Apoptosis ,Tauopathy ,Oxidation-Reduction ,030217 neurology & neurosurgery ,Protein Binding - Abstract
BackgroundAlzheimer’s disease (AD) is an irreversible neurodegenerative disease without a cure or prevention to date. The defining features of AD include neurofibrillary tangles (NFTs) of hyperphosphorylated tau fibrils, and the senile plaques of β amyloid (Aβ) aggregates. In addition to AD, aggregation of hyperphosphorylated tau underlies approximately 20 neurodegenerative disorders collectively known as tauopathies, suggesting a pathogenic role of tau fibrils. The majority of AD disease-modifying drug trials targeted Aβ control, which have yet to produce satisfactory outcomes. The interest of developing anti-NFT drugs has been increasing. However, an effective method that produces hyperphosphorylated tau with disease relevant characters to support drug discovery is lacking.MethodsWe previously reported the PIMAX system for the production of recombinant proteins bearing a desired post-translational modification. Here we use PIMAX to express hyperphosphorylated tau (p-tau) in E. coli, and subjected this p-tau to mass spectrometry mapping of phosphorylation, to biochemical and biophysical assays of fibrillogenesis, and to cell culture treatment for the effects of hyperphosphorylation on tau molecular characters.ResultsMass spectrometry mapped p-tau phosphorylation to phosphoepitopes linked to AD pathological progression. In stark contrast to the unmodified tau that required an inducer for efficient aggregation, and which had only mild effects on cell functions, p-tau formed fibrils in an inducer-free and redox-independent manner. Immediately after the purification, a disease-specific conformation recognized by the MC-1 monoclonal antibody was readily detectable, which continued to increase during the fibrillization reaction. When applied to cultured cells, p-tau triggered a spike of mitochondrial superoxide, induced apoptosis, and caused cell death at sub-micromolar concentrations. In both aggregation and cytotoxicity assays, p-tau exhibited seeding activities that converted the unmodified tau into a cytotoxic species with increased propensity for fibrillization, consistent with the emerging view that hyperphosphorylated tau spreads in a prion-like fashion.ConclusionsHyperphosphorylation potentiates tau fibrillization and cytotoxicity. These characters are consistent with the model that abnormally phosphorylated tau plays a direct role in neurodegeneration in tauopathies. We suggest that p-tau produced by PIMAX affords a feasible tool for drug discovery and disease mechanistic studies for Alzheimer's disease and other tauopathies.
- Published
- 2020
37. Abstract 288: Revisiting small molecules that influence the nuclear translocation of thioredoxin-1, prohibitin, and galectin-3 for cancer chemotherapy
- Author
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Kelsey E. Duggan, René C.-Gaudreault, Jessica S. Fortin, and Thomas E. Wineland
- Subjects
Cancer Research ,Cancer chemotherapy ,Oncology ,Galectin-3 ,Chemistry ,Cancer research ,Thioredoxin-1 ,Prohibitin ,Small molecule ,Nuclear translocation - Abstract
Phenyl-3-(2-chloroethyl)ureas (CEU) are alkylating agents exhibiting potent antiproliferative properties both in vitro and in vivo. CEUs' cytoxicity is not influenced by hypoxia or other clinically relevant mechanisms of chemoresistance, such as alteration of topoisomerase II activity and increased P-glycoprotein over-expression, DNA repair, intracellular gluthatione-S-transferase activity. A first subset of CEU exemplified by the prototypical molecules 4-tert-butyl-CEU (tBCEU) and 4-iodo-CEU (ICEU) have been shown to alkylate the colchicine-binding site on βII-tubulin. In parallel, these molecules disrupted the cytoskeleton and arrested the cell cycle in G2/M leading to anoikis. So far we have conducted several structure-activity relationship and molecular pharmacology studies in an attempt to refine the specificity of CEU for β-tubulin and the colchicine-binding site. Unexpectedly, a prototypical molecule designated as 1-(2-chloroethyl)-3-(4-cyclohexylphenyl)urea (cHCEU) emerged as arresting the cell cycle in G0/G1 phase instead of G2/M. Experiments using [14C-urea]-cHCEU showed its binding to thioredoxin isoform-1 (Trx-1) and prohibitin (PHB), but not β-tubulin. Complementary immunocytofluorometry experiments clearly showed the abrogation of the nuclear translocation of Trx-1 from the cytosol. We report herein that in addition to Trx-1 and PHB, cHCEU also alkylates galectin-1 and -3 isoforms. The cellular localization of thioredoxin-1, prohibitin, and galectin-3 (Gal-3) is changed following cHCEU treatment. In addition, the expression of Trx-1, PHB, and Gal-3 seems unaffected by CEU and its analogues. Interestingly, these proteins are all known to play an important role in the cell cycle regulation through various mechanisms. The mechanism(s) underlying the effect of cHCEU on protein translocation is unknow and might be relevant to design new potent anticancer drugs that will target specific and lethal biological pathways essential to tumor growth. Citation Format: Jessica S. Fortin, Thomas E. Wineland, Kelsey E. Duggan, René C.-Gaudreault. Revisiting small molecules that influence the nuclear translocation of thioredoxin-1, prohibitin, and galectin-3 for cancer chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 288.
- Published
- 2021
38. INTESTINAL HISTOPLASMOSIS IN A CAPTIVE REINDEER (RANGIFER TARANDUS), MISSOURI, USA
- Author
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Dusty W Nagy, Keiichi Kuroki, Michael J. Calcutt, and Jessica S. Fortin
- Subjects
Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,040301 veterinary sciences ,animal diseases ,030106 microbiology ,Zoology ,Insomnia, Fatal Familial ,Histoplasma capsulatum ,Histoplasmosis ,0403 veterinary science ,03 medical and health sciences ,fluids and secretions ,parasitic diseases ,medicine ,Animals ,Intestinal Diseases, Parasitic ,Enterocolitis ,Missouri ,General Veterinary ,biology ,Endemic area ,04 agricultural and veterinary sciences ,General Medicine ,bacterial infections and mycoses ,medicine.disease ,biology.organism_classification ,Tissue sections ,Animal Science and Zoology ,medicine.symptom ,Dimorphic fungus ,Reindeer - Abstract
An infection with Histoplasma capsulatum was diagnosed in a farmed reindeer in Missouri, an endemic area for histoplasmosis, localized in the intestine. The intrahistiocytic organisms were identified in tissue sections using histologic methods and confirmed by immunohistochemistry. This is the first report of histoplasmosis in a reindeer or in any deer species.
- Published
- 2017
39. Methods Optimization for Routine Sciatic Nerve Processing in General Toxicity Studies
- Author
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Daniel P Shaw, Elizabeth A Chlipala, Brad Bolon, and Jessica S. Fortin
- Subjects
Tissue Fixation ,040301 veterinary sciences ,Swine ,H&E stain ,Nerve fiber ,Toxicology ,030226 pharmacology & pharmacy ,Pathology and Forensic Medicine ,Specimen Handling ,0403 veterinary science ,03 medical and health sciences ,Fixatives ,0302 clinical medicine ,Formaldehyde ,Toxicity Tests ,medicine ,Animals ,Rats, Wistar ,Molecular Biology ,Fixative ,Fixation (histology) ,Chemistry ,04 agricultural and veterinary sciences ,Cell Biology ,Immunohistochemistry ,Sciatic Nerve ,Staining ,Rats ,medicine.anatomical_structure ,Anesthesia ,Peripheral nervous system ,Toxicity ,Sciatic nerve - Abstract
Recent “best practice” recommendations for peripheral nervous system sampling and processing provide guidance regarding nerve preparation for animal toxicity studies. This study explored the impact of delayed fixation, type of fixative, processing cycle times, starting ethanol concentration, and water bath temperature to improve nerve preservation in routinely prepared (paraffin-embedded, hematoxylin and eosin [H&E]-stained) sections. Sciatic nerves from adult Wistar rats (diameter, 1.04 ± 0.1 mm) and young domestic pigs (diameter 5.9 ± 1.2 mm) fixed at necropsy (“0” hours) or 3, 6, 12, or 24 hours after death were immersed in neutral-buffered 10% formalin containing 1.2% methanol (NBF) or methanol-free 4% formaldehyde (MFF) at room temperature. After fixation for 24 hours (rat) or 48 hours (pig), specimens were processed into paraffin, and ∼5-μm-thick sections were flattened on water baths set at 35°C, 40°C, or 45°C before H&E staining. Large-diameter nerves (pig) required longer processing cycles to ensure sufficient paraffin infiltration. For both small-diameter (rat) and large-diameter nerves, structural integrity was optimal if fixation by NBF or MFF occurred within 3 hours and the initial ethanol concentration for tissue processing was lowered to 50%. At all time points, structural preservation of nerve fibers was acceptable using NBF but was better with MFF. Use of a water bath at 35°C reduced processing-related nerve fiber separation within sections.
- Published
- 2019
40. Contributors
- Author
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Arturo Anadón, Vellareddy Anantharam, Anthony E. Archibong, Irma Ares, Adam D. Aulbach, Nikee Awasthee, Aryamitra Banerjee, Leah D. Banks, Frank A. Barile, Sudheer R. Beedanagari, Charalampos Belantis, Enrico Bergamaschi, Sadikshya Bhandari, Sneha P. Bhatia, Karyn Bischoff, David J. Borts, Emily Brehm, Subash Chandra Gupta, Saurabh Chatterjee, Catheryne Chiang, Anirudh J. Chintalapati, P. Cohn, Robert W. Coppock, Lucio G. Costa, Tirupapuliyur V. Damodaran, Clinton D'Souza, Wolf-D. Dettbarn, Amy A. Devlin, Robin B. Doss, Shiwangi Dwivedi, Margitta M. Dziwenka, Jorge Estévez, Daniel S. Fabricant, A.M. Fan, Vanessa A. Fitsanakis, John Flaskos, Jodi A. Flaws, Swaran J.S. Flora, Sue M. Ford, Jessica S. Fortin, Domniki Fragou, Shayne C. Gad, Bianca Galateanu, Dale R. Gardner, George Georgiadis, Fernando Gil, Saryu Goel, Mary Gulumian, P.K. Gupta, Ramesh C. Gupta, Rekha K. Gupta, Sharon Gwaltney-Brant, Alan J. Hargreaves, Kelly L. Harris, Kenneth J. Harris, Holly E. Hatfield, Wallace A. Hayes, Ioannis Heretis, Antonio F. Hernández, Corey J. Hilmas, Darryl B. Hood, Pasi Huuskonen, Stewart B. Jacobson, Sandra A. James-Yi, Huajun Jin, Jun Kanno, Arthi Kanthasamy, Anumantha G. Kanthasamy, Shilpa N. Kaore, Navinchandra M. Kaore, Bhupendra S. Kaphalia, Vesa Karttunen, Gurjot Kaur, Ravneet Kaur, Prasada Rao S. Kodavanti, Urmila P. Kodavanti, George A. Kontadakis, Gopala Krishna, Priya A. Krishna, Kavya A. Krishna, Maria Kummu, George D. Kymionis, Rajiv Lall, P. Lin, Bommanna G. Loganathan, Jarkko Loikkanen, Marcello Lotti, Michael A. Lynes, Brinda Mahadevan, Jitendra K. Malik, Charalampos Mamoulakis, Jane A. Mantey, María Rosa Martínez-Larrañaga, María Aránzazu Martínez, Charalampos Mavridis, Roger O. McClellan, Vincent P. Meador, Lars Friis Mikkelsen, Dejan Milatovic, Ida R. Miller Mukherjee, Anupama Mukherjee, Pushpinder Kaur Multani, Päivi Myllynen, Kirsi Myöhänen, Rekek Negga, Carolina Negrei, Meliton N. Novilla, Stephanie Padilla, Carlos M. Palmeira, Kip E. Panter, Markku Pasanen, Daniel J. Patrick, Sofia Pavanello, Henrik Duelund Pedersen, Olavi Pelkonen, Michael A. Pellizzon, Jason Pitt, Argyro Plaka, Aramandla Ramesh, Saniya Rattan, Jenni Repo, Matthew R. Ricci, Anabela P. Rolo, Magdalini Sachana, Heidi Sahlman, Nitin Saini, Vandana Saini, Kai Savolainen, Ratanesh Kumar Seth, Abha Sharma, Anurag Sharma, Elina Sieppi, Rui Silva, Anita Sinha, Iordanis Skamagkas, Samantha J. Snow, Miguel A. Sogorb, Ajay Srivastava, Szabina A. Stice, Markus Storvik, David T. Szabo, João S. Teodoro, Aristidis M. Tsatsakis, John Tsiaoussis, Kirsi Vähäkangas, Sumit Singh Verma, Eugenio Vilanova, Suryanarayana V. Vulimiri, Genoa R. Warner, Kevin D. Welch, Christina Wilson-Frank, S.H. You, Snjezana Zaja-Milatovic, Ioannis E. Zisis, and Csaba K. Zoltani
- Published
- 2019
41. Discovery of ethyl urea derivatives as inhibitors of islet amyloid polypeptide fibrillization and cytotoxicity
- Author
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Marie-Odile Benoit-Biancamano, René C-Gaudreault, and Jessica S. Fortin
- Subjects
0301 basic medicine ,Amyloid ,Physiology ,Small Molecule Libraries ,Islets of Langerhans ,03 medical and health sciences ,Physiology (medical) ,medicine ,Humans ,Urea ,Moiety ,Cytotoxicity ,Pharmacology ,geography ,geography.geographical_feature_category ,030102 biochemistry & molecular biology ,Chemistry ,Amyloidosis ,Pancreatic islets ,General Medicine ,medicine.disease ,Islet ,Small molecule ,In vitro ,Islet Amyloid Polypeptide ,030104 developmental biology ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,Biochemistry - Abstract
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.
- Published
- 2016
42. Small molecules breaking down islet amyloid polypeptide self‐assembly
- Author
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Thomas L. Thompson, Malikah O’Dell, Jessica S. Fortin, Anisa M. Rashid, and Nurhanis B.M. Isa
- Subjects
geography ,geography.geographical_feature_category ,Amyloid ,Chemistry ,Genetics ,Biophysics ,Self-assembly ,Islet ,Molecular Biology ,Biochemistry ,Small molecule ,Biotechnology - Published
- 2020
43. Design of Small Molecules to Modulate Transthyretin Aggregation
- Author
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Nurhanis B.M. Isa, Malikah O’Dell, Anisa M. Rashid, Thomas L. Thompson, and Jessica S. Fortin
- Subjects
Transthyretin ,biology ,Chemistry ,Genetics ,Biophysics ,biology.protein ,Molecular Biology ,Biochemistry ,Small molecule ,Biotechnology - Published
- 2020
44. Concurrent thoracic mesothelioma and thyroid C-cell adenoma with amyloid deposition in an aged horse
- Author
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Jessica S. Fortin, Keiichi Kuroki, and Angela B. Royal
- Subjects
Mesothelioma ,Pathology ,medicine.medical_specialty ,Amyloid ,Adenoma ,040301 veterinary sciences ,Pleural effusion ,Case Report ,Case Reports ,Thyroid adenoma ,0403 veterinary science ,03 medical and health sciences ,0302 clinical medicine ,Aged horse ,medicine ,C‐cell adenoma ,General Veterinary ,Thoracic cavity ,business.industry ,Equine ,Thyroid ,04 agricultural and veterinary sciences ,medicine.disease ,medicine.anatomical_structure ,Calcitonin ,030220 oncology & carcinogenesis ,Histopathology ,business - Abstract
A 21‐year‐old American Saddlebred mare died with a history of weight loss and breathing difficulties of 1 month duration. Post‐mortem examination revealed a copious pleural effusion with multifocal to coalescing numerous white to grey nodular masses on the serosal surface of the pericardium, lungs and thoracic cavity. In addition, the left thyroid gland was markedly enlarged. A thoracic mesothelioma and C‐cell adenoma with amyloid deposits of the left thyroid gland were diagnosed by histopathology and confirmed by immunohistochemistry employing antibodies against cytokeratin (CK), vimentin and calcitonin. Amyloid deposits in the thyroid tumour were confirmed by Congo red staining with apple‐green birefringence under polarized light. Mesothelioma remains an uncommon neoplasm encountered in aged horses. Discussion includes the diagnostic challenge of differentiating carcinomatosis from mesothelioma by histology and differentiating reactive and neoplastic mesothelial cells by cytology.
- Published
- 2018
45. What is your diagnosis? Nasopharyngeal mass in a mixed breed dog
- Author
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Angela B. Royal, Fred Williams, Jessica S. Fortin, and Jeremy L. Shomper
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,General Veterinary ,business.industry ,Nose Neoplasms ,Nasopharyngeal neoplasm ,Pharyngeal Neoplasms ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Dogs ,Epistaxis ,Mixed breed dog ,030220 oncology & carcinogenesis ,Medicine ,Animals ,Female ,Dog Diseases ,Mast Cells ,business - Published
- 2018
46. Sublingual pythiosis in a cat
- Author
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Dae Young Kim, Michael J. Calcutt, and Jessica S. Fortin
- Subjects
Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,040301 veterinary sciences ,Pythium insidiosum ,030106 microbiology ,Hyphae ,Case Report ,Pythium ,Eosinophilic granulomatous inflammation ,Cat Diseases ,Oral cavity ,Feline ,Diagnosis, Differential ,0403 veterinary science ,Granulomatous inflammation ,03 medical and health sciences ,Pythiosis ,Eosinophilic ,medicine ,Animals ,Gastrointestinal tract ,lcsh:Veterinary medicine ,Missouri ,General Veterinary ,biology ,04 agricultural and veterinary sciences ,General Medicine ,Sublingual mass ,biology.organism_classification ,Cats ,Amplicon sequencing ,lcsh:SF600-1100 ,Mouth Diseases - Abstract
Background Pythiosis is a potentially fatal but non-contagious disease affecting humans and animals living in tropical and subtropical climates, but is also reasonably widespread in temperate climates, throughout the world. The most commonly reported affected animal species with pythiosis are equine and canine, with fewer cases in bovine and feline. Extracutaneous infections caused by Pythium insidiosum have been rarely described in the cat. Case presentation Sublingual pythiosis was diagnosed in a 2-year-old, male, Domestic Shorthair cat. The cat had a multilobulated, sublingual mass present for 3 months. Histopathological examination revealed severe multifocal coalescing eosinophilic granulomatous inflammation. Centers of the inflammation contained hyphae that were 3–7 μm-wide, non-parallel, uncommonly septate and rarely branching. The fungal-like organism was identified as P. insidiosum by polymerase chain reaction and subsequent amplicon sequencing. Conclusions Only a few feline pythiosis cases have been reported and, when encountered, it usually causes granulomatous diseases of the skin or gastrointestinal tract. This case presents an unusual manifestation of feline pythiosis, representing the first involving the oral cavity in cats or dogs.
- Published
- 2017
47. Inhibition of islet amyloid polypeptide aggregation and associated cytotoxicity by nonsteroidal anti-inflammatory drugs
- Author
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Jessica S. Fortin and Marie-Odile Benoit-Biancamano
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Amyloid ,Physiology ,Pharmacology ,In Vitro Techniques ,Piroxicam ,Protein Aggregation, Pathological ,Protein Structure, Secondary ,Cell Line ,03 medical and health sciences ,Protein Aggregates ,Structure-Activity Relationship ,Diclofenac ,Tenoxicam ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Humans ,Sulindac ,business.industry ,Amyloidosis ,Anti-Inflammatory Agents, Non-Steroidal ,General Medicine ,medicine.disease ,digestive system diseases ,Islet Amyloid Polypeptide ,Rats ,Meloxicam ,030104 developmental biology ,Endocrinology ,Cats ,Protein Multimerization ,business ,Nimesulide ,medicine.drug - Abstract
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.
- Published
- 2015
48. Chloroethyl urea derivatives block tumour growth and thioredoxin-1 nuclear translocation
- Author
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Jacques Lacroix, Eric Petitclerc, René C.-Gaudreault, Alexandre Patenaude, Réna DeschenesR. Deschenes, Marie-France Côté, and Jessica S. Fortin
- Subjects
Physiology ,Active Transport, Cell Nucleus ,Biology ,Catalysis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Thioredoxins ,In vivo ,Cell Line, Tumor ,Physiology (medical) ,medicine ,Humans ,Urea ,Structure–activity relationship ,Antineoplastic Agents, Alkylating ,Cell Proliferation ,Cell Nucleus ,Pharmacology ,Cisplatin ,Cell growth ,Aryl ,General Medicine ,In vitro ,Protein Transport ,Biochemistry ,chemistry ,Thioredoxin ,medicine.drug - Abstract
Aryl chloroethyl ureas (CEUs) are new protein alkylating agents exhibiting anticancer activity both in vitro and in vivo. We report herein that14C-labeled CEU derivatives, designated CEU-025 and CEU-027, covalently bind to thioredoxin-1 (TRX1). Covalent binding of these molecules slightly decreases the disulfide-reducing activity of recombinant TRX1, when compared with the effect of strong thioalkylating agents such as N-ethylmaleimide. Moreover, site-directed mutagenesis and diamide competition assays demonstrated that TRX1 cysteinyl residues are not the prime targets of CEUs. CEU-025 abrogates the nuclear translocation of TRX1 in human cancer cells. In addition, we show that CEU-025 can block TRX1 nuclear translocation induced by cisplatin. Unexpectedly, pretreatment with sublethal CEU-025 concentrations that block TRX1 nuclear translocation protected the cells against cisplatin cytotoxicity. Overexpression of TRX1 in HT1080 fibrosarcoma cells attenuated CEU-025 cytotoxicity, while its suppression using TRX1-specific siRNA increased the effects of CEU-025, suggesting that loss of function of TRX1 is involved, at least in part, in the cytotoxic activity of CEU-025. These results suggest that CEU-025 and CEU-027 exhibit anticancer activity through a novel, unique mechanism of action. The importance of TRX1 and the dependence of the cytotoxicity of CEU-025 and CEU-027 on TRX1 intracellular localization are also discussed.
- Published
- 2010
49. Aromatic 2-chloroethyl urea derivatives and bioisosteres. Part 2: Cytocidal activity and effects on the nuclear translocation of thioredoxin-1, and the cell cycle progression
- Author
-
René C.-Gaudreault, Jacques Lacroix, Eric Petitclerc, Jessica S. Fortin, and Marie-France Côté
- Subjects
Clinical Biochemistry ,Active Transport, Cell Nucleus ,Pharmaceutical Science ,Antineoplastic Agents ,Chromosomal translocation ,Biochemistry ,Structure-Activity Relationship ,Thioredoxins ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Urea ,Structure–activity relationship ,Molecular Biology ,Molecular Structure ,Chemistry ,Cell Cycle ,Organic Chemistry ,Biological activity ,Cell cycle ,Cell nucleus ,medicine.anatomical_structure ,Cell culture ,Molecular Medicine ,Thioredoxin ,Intracellular - Abstract
Recently, a subset of N-phenyl-N'-(2-chloroethyl)ureas (CEU) was found abrogating the nuclear translocation of thioredoxin-1 and arresting the cell cycle in G(0)/G(1) phase. Several derivatives were prepared to assess their effect on cell cycle progression and on the intracellular location of Trx-1. Compounds 1-20, 21-40, and 41-60 exhibited GI(50) between 1 and 80 microM. Immunocytochemistry analysis showed compounds 4, 6, 8, 10, 11, 23, 24, 26-31, 34, 37, 41, 44, 46-51, 53, 56, and 57 inhibiting the nuclear translocation of Trx-1. Our results suggest that increasing the electrophilic character of these molecules might enhance the antiproliferative activity at the expense of the selectivity toward thioredoxin-1 and the G(0)/G(1) phase arrest.
- Published
- 2008
50. Wildlife sequences of islet amyloid polypeptide (IAPP) identify critical species variants for fibrillization
- Author
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Jessica S. Fortin and Marie-Odile Benoit-Biancamano
- Subjects
Gene isoform ,In silico ,Amino Acid Motifs ,Molecular Sequence Data ,Gene Expression ,Sequence alignment ,Animals, Wild ,Biology ,Bioinformatics ,Fibril ,Islets of Langerhans ,Structure-Activity Relationship ,Species Specificity ,Peptide Library ,Gene expression ,Internal Medicine ,medicine ,Animals ,Humans ,Peptide library ,Phylogeny ,Genetics ,geography ,geography.geographical_feature_category ,Amyloid beta-Peptides ,Amyloidosis ,medicine.disease ,Islet ,Islet Amyloid Polypeptide ,Diabetes Mellitus, Type 2 ,Sequence Alignment - Abstract
Amyloid can be detected in the islets of Langerhans in a majority of type 2 diabetic patients. These deposits have been associated with β-cell death, thereby furthering diabetes progression. Islet amyloid polypeptide (IAPP) amyloidogenicity is quite variable among animal species, and studying this variability could further our understanding of the mechanisms involved in the aggregation process. Thus, the general aim of this study was to identify IAPP isoforms in different animal species and characterize their propensity to form fibrillar aggregates. A library of 23 peptides (fragment 8-32) was designed to study the amyloid formation using in silico analysis and in vitro assays. Amyloid formation was impeded when the NFLVH motif found in segment 8-20 was substituted by DFLGR or KFLIR segments. A 29P, 14K and 18R substitution were often present in non-amyloidogenic sequences. Non-amyloidogenic sequences were obtained from Leontopithecus rosalia, Tursiops truncatus and Vicugna pacos. Fragment peptides from 34 species were amyloidogenic. To conclude, this project advances our knowledge on the comparative pathogenesis of amyloidosis in type II diabetes. It is conceivable that the additional information gained may help point towards new therapeutic strategies for diabetes patients.
- Published
- 2015
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