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https://www.readbyqxmd.com/read/28334940/aav9-delivered-bispecific-nanobody-attenuates-amyloid-burden-in-the-gelsolin-amyloidosis-mouse-model
#1
Adriaan Verhelle, Nisha Nair, Inge Everaert, Wouter Van Overbeke, Lynn Supply, Olivier Zwaenepoel, Cindy Peleman, Jo Van Dorpe, Tony Lahoutte, Nick Devoogdt, Wim Derave, Marinee K Chuah, Thierry Vanden Driessche, Jan Gettemans
Gelsolin amyloidosis is a dominantly inherited, incurable type of amyloidosis. A single point mutation in the gelsolin gene (G654A is most common) results in the loss of a Ca2+  binding site in the second gelsolin domain. Consequently, this domain partly unfolds and exposes an otherwise buried furin cleavage site at the surface. During secretion of mutant plasma gelsolin consecutive cleavage by furin and MT1-MMP results in the production of 8 and 5 kDa amyloidogenic peptides. Nanobodies that are able to (partly) inhibit furin or MT1-MMP proteolysis have previously been reported...
February 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28334907/a-combinatorial-approach-to-identify-calpain-cleavage-sites-in-the-machado-joseph-disease-protein-ataxin-3
#2
Jonasz J Weber, Matthias Golla, Giambattista Guaitoli, Pimthanya Wanichawan, Stefanie N Hayer, Stefan Hauser, Ann-Christin Krahl, Maike Nagel, Sebastian Samer, Eleonora Aronica, Cathrine R Carlson, Ludger Schöls, Olaf Riess, Christian J Gloeckner, Huu P Nguyen, Jeannette Hübener-Schmid
Ataxin-3, the disease protein in Machado-Joseph disease, is known to be proteolytically modified by various enzymes including two major families of proteases, caspases and calpains. This processing results in the generation of toxic fragments of the polyglutamine-expanded protein. Although various approaches were undertaken to identify cleavage sites within ataxin-3 and to evaluate the impact of fragments on the molecular pathogenesis of Machado-Joseph disease, calpain-mediated cleavage of the disease protein and the localization of cleavage sites remained unclear...
March 8, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28334815/gcn5-mediated-rph1-acetylation-regulates-its-autophagic-degradation-under-dna-damage-stress
#3
Feng Li, Liang-De Zheng, Xin Chen, Xiaolu Zhao, Scott D Briggs, Hai-Ning Du
Histone modifiers regulate proper cellular activities in response to various environmental stress by modulating gene expression. In budding yeast, Rph1 transcriptionally represses many DNA damage or autophagy-related gene expression. However, little is known how Rph1 is regulated during these stress conditions. Here, we report that Rph1 is degraded upon DNA damage stress conditions. Notably, this degradation occurs via the autophagy pathway rather than through 26S proteasome proteolysis. Deletion of ATG genes or inhibition of vacuole protease activity compromises Rph1 turnover...
February 21, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334762/missense-uros-mutations-causing-congenital-erythropoietic-porphyria-reduce-uros-homeostasis-that-can-be-rescued-by-proteasome-inhibition
#4
Jean-Marc Blouin, Ganeko Bernardo-Seisdedos, Emma Sasso, Julie Esteve, Cécile Ged, Magalie Lalanne, Arantza Sanz-Parra, Pedro Urquiza, Hubert de Verneuil, Oscar Millet, Emmanuel Richard
Congenital erythropoietic porphyria (CEP) is an inborn error of heme biosynthesis characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in deleterious porphyrin accumulation in blood cells responsible for hemolytic anemia and cutaneous photosensitivity. We analyzed here the molecular basis of UROS impairment associated with twenty nine UROS missense mutations actually described in CEP patients. Using a computational and biophysical joint approach we predicted that most disease-causing mutations would affect UROS folding and stability...
February 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28333093/the-effect-of-regular-intake-of-dry-cured-ham-rich-in-bioactive-peptides-on-inflammation-platelet-and-monocyte-activation-markers-in-humans
#5
Sara María Martínez-Sánchez, Alfredo Minguela, David Prieto-Merino, María Pilar Zafrilla-Rentero, José Abellán-Alemán, Silvia Montoro-García
Background and aims: Dietary studies have shown that active biopeptides provide protective health benefits, although the mediating pathways are somewhat uncertain. To throw light on this situation, we studied the effects of consuming Spanish dry-cured ham on platelet function, monocyte activation markers and the inflammatory status of healthy humans with pre-hypertension. Methods: Thirty-eight healthy volunteers with systolic blood pressure of >125 mmHg were enrolled in a two-arm crossover randomized controlled trial...
March 23, 2017: Nutrients
https://www.readbyqxmd.com/read/28331908/il-1%C3%AE-is-an-innate-immune-sensor-of-microbial-proteolysis
#6
Christopher N LaRock, Jordan Todd, Doris L LaRock, Joshua Olson, Anthony J O'Donoghue, Avril A B Robertson, Matthew A Cooper, Hal M Hoffman, Victor Nizet
Interleukin-1β (IL-1β) is a key proinflammatory cytokine that drives antimicrobial immune responses. IL-1β is aberrantly activated in autoimmune diseases, and IL-1β inhibitors are used as therapeutic agents to treat patients with certain autoimmune disorders. Review of postmarketing surveillance of patients receiving IL-1β inhibitors found a disproportionate reporting of invasive infections by group A Streptococcus (GAS). IL-1β inhibition increased mouse susceptibility to GAS infection, but IL-1β was produced independent of canonical inflammasomes...
August 2016: Science Immunology
https://www.readbyqxmd.com/read/28330496/calcium-dysregulation-functional-calpainopathy-and-endoplasmic-reticulum-stress-in-sporadic-inclusion-body-myositis
#7
David R Amici, Iago Pinal-Fernandez, Davi A G Mázala, Thomas E Lloyd, Andrea M Corse, Lisa Christopher-Stine, Andrew L Mammen, Eva R Chin
Sporadic inclusion body myositis (IBM) is the most common primary myopathy in the elderly, but its pathoetiology is still unclear. Perturbed myocellular calcium (Ca(2+)) homeostasis can exacerbate many of the factors proposed to mediate muscle degeneration in IBM, such as mitochondrial dysfunction, protein aggregation, and endoplasmic reticulum stress. Ca(2+) dysregulation may plausibly be initiated in IBM by immune-mediated membrane damage and/or abnormally accumulating proteins, but no studies to date have investigated Ca(2+) regulation in IBM patients...
March 22, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28330493/loss-of-mmp-8-in-ductal-carcinoma-in-situ-dcis-associated-myoepithelial-cells-contributes-to-tumour-promotion-through-altered-adhesive-and-proteolytic-function
#8
Muge Sarper, Michael D Allen, Jenny Gomm, Linda Haywood, Julie Decock, Sally Thirkettle, Ahsen Ustaoglu, Shah-Jalal Sarker, John Marshall, Dylan R Edwards, J Louise Jones
BACKGROUND: Normal myoepithelial cells (MECs) play an important tumour-suppressor role in the breast but display an altered phenotype in ductal carcinoma in situ (DCIS), gaining tumour-promoter functions. Matrix metalloproteinase-8 (MMP-8) is expressed by normal MECs but is lost in DCIS. This study investigated the function of MMP-8 in MECs and the impact of its loss in DCIS. METHODS: Primary normal and DCIS-associated MECs, and normal (N-1089) and DCIS-modified myoepithelial (β6-1089) cell lines, were used to assess MMP-8 expression and function...
March 23, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28329063/lysosomal-proteolysis-is-associated-with-exercise-induced-improvement-of-mitochondrial-quality-control-in-aged-hippocampus
#9
Li Luo, Jia-Ru Dai, Shan-Shan Guo, A-Ming Lu, Xiao-Fang Gao, Yan-Rong Gu, Xiao-Fei Zhang, Hai-Dong Xu, Yan Wang, Zhou Zhu, Lisa J Wood, Zheng-Hong Qin
Exercise improves cognitive function in older adults, but the underlying mechanism is largely unknown. Both lysosomal degradation and mitochondrial quality control decline with age. We hypothesized that exercise ameliorates age-related cognitive decline through the improvement of mitochondrial quality control in aged hippocampus, and this effect is associated with lysosomal proteolysis. Sixteen to eighteen-month old male Sprague Dawley rats underwent swim exercise training for 10 weeks. The exercise regimen prevented cognitive decline in aged rats, reduced oxidative stress, and rejuvenated mitochondria in the aged hippocampus...
January 19, 2017: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/28324011/a-novel-fc-fgf21-with-improved-resistance-to-proteolysis-increased-affinity-towards-%C3%AE-klotho-and-enhanced-efficacy-in-mice-and-cynomolgus-monkeys
#10
Shanaka Stanislaus, Randy Hecht, Junming Yie, Todd Hager, Michael Hall, Chris Spahr, Wei Wang, Jennifer Weiszmann, Yang Li, Liying Deng, Dwight Winters, Stephen Smith, Lei Zhou, Yuesheng Li, Murielle M Véniant, Jing Xu
FGF21 is a natural hormone that modulates glucose, lipid, and energy metabolism. Previously, we engineered an Fc fusion FGF21 variant with two mutations, Fc-FGF21(RG), to extend the half-life and reduce aggregation and in vivo degradation of FGF21. We now describe a new variant developed to reduce the extreme C-terminal degradation and improve the binding affinity to β-Klotho. We demonstrate, by introducing one additional mutation located at the C-terminus of FGF21 (A180E) that the new molecule, Fc-FGF21(RGE), has gained many improved attributes...
January 26, 2017: Endocrinology
https://www.readbyqxmd.com/read/28323982/versican-proteolysis-by-adamts-proteases-and-its-influence-on-sex-steroid-receptor-expression-in-uterine-leiomyoma
#11
Ndeye-Aicha Gueye, Timothy J Mead, Christopher D Koch, Charles V Biscotti, Tommaso Falcone, Suneel S Apte
Context: Leiomyomas have abundant extracellular matrix (ECM), with upregulation of versican, a large proteoglycan. Objective: To investigate ADAMTS protease-mediated versican cleavage in myometrium and leiomyoma and the effect of versican knockdown in leiomyoma cells. Design: We used qRT-PCR, western blotting, immunohistochemistry and RNA in situ hybridization for analysis of myometrium, leiomyoma, and immortalized myometrium and leiomyoma cells...
February 6, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28323844/nuclear-localization-of-amyloid-%C3%AE-precursor-protein-binding-protein-fe65-is-dependent-on-regulated-intramembrane-proteolysis
#12
Niina A Koistinen, Anna K Edlund, Preeti K Menon, Elena V Ivanova, Smaranda Bacanu, Kerstin Iverfeldt
Fe65 is an adaptor protein involved in both processing and signaling of the Alzheimer-associated amyloid-β precursor protein, APP. Here, the subcellular localization was further investigated using TAP-tagged Fe65 constructs expressed in human neuroblastoma cells. Our results indicate that PTB2 rather than the WW domain is important for the nuclear localization of Fe65. Electrophoretic mobility shift of Fe65 caused by phosphorylation was not detected in the nuclear fraction, suggesting that phosphorylation could restrict nuclear localization of Fe65...
2017: PloS One
https://www.readbyqxmd.com/read/28323513/transmembrane-tnf-dependent-uptake-of-anti-tnf-antibodies
#13
Arun Deora, Subramanya Hegde, Jacqueline Lee, Chee-Ho Choi, Qing Chang, Cheryl Lee, Lucia Eaton, Hua Tang, Dongdong Wang, David Lee, Mark Michalak, Medha Tomlinson, Qingfeng Tao, Nidhi Gaur, Bohdan Harvey, Shaun McLoughlin, Boris Labkovsky, Tariq Ghayur
TNF-alpha (TNF), a pro-inflammatory cytokine is synthesized as a 26 kDa protein, anchors in the plasma membrane as transmembrane TNF (TmTNF), and is subjected to proteolysis by the TNF-alpha converting enzyme (TACE) to release the 15 kDa form of soluble TNF (sTNF). TmTNF and sTNF interact with two distinct receptors, TNF-R1 (p55) and TNF-R2 (p75), to mediate the multiple biological effects of TNF described to date. Several anti-TNF biologics that bind to both forms of TNF and block their interactions with the TNF receptors are now approved for the treatment of a variety of immune-mediated diseases...
March 21, 2017: MAbs
https://www.readbyqxmd.com/read/28323038/monocular-denervation-of-visual-nuclei-modulates-app-processing-and-sapp%C3%AE-production-a-possible-role-on-neural-plasticity
#14
Juliana Ferreira Vasques, Pedro Vinícius Bastos Heringer, Renata Guedes de Jesus Gonçalves, Paula Campello-Costa, Claudio Alberto Serfaty, Adriana da Cunha Faria-Melibeu
Amyloid precursor protein (APP) is essential to physiological processes such as synapse formation and neural plasticity. Sequential proteolysis of APP by beta- and gamma-secretases generates amyloid-beta peptide (Aβ), the main component of senile plaques in Alzheimer Disease. Alternative APP cleavage by alpha-secretase occurs within Aβ domain, releasing soluble α-APP (sAPPα), a neurotrophic fragment. Among other functions, sAPPα is important to synaptogenesis, neural survival and axonal growth. APP and sAPPα levels are increased in models of neuroplasticity, which suggests an important role for APP and its metabolites, especially sAPPα, in the rearranging brain...
March 16, 2017: International Journal of Developmental Neuroscience
https://www.readbyqxmd.com/read/28322282/maternal-immune-activation-dysregulation-of-the-fetal-brain-transcriptome-and-relevance-to-the-pathophysiology-of-autism-spectrum-disorder
#15
M V Lombardo, H M Moon, J Su, T D Palmer, E Courchesne, T Pramparo
Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations...
March 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28320353/genome-independent-hypoxic-repression-of-estrogen-receptor-alpha-in-breast-cancer-cells
#16
Mercè Padró, Raymond J Louie, Brian V Lananna, Adam J Krieg, Luika A Timmerman, Denise A Chan
BACKGROUND: About 75-80% of breast tumors express the estrogen receptor alpha (ER-α) and are treated with endocrine-target therapeutics, making this the premier therapeutic modality in the breast cancer clinic. However, acquired resistance is common and about 20% of resistant tumors loose ER-α expression via unknown mechanisms. Inhibition of ER-α loss could improve endocrine therapeutic efficacy, benefiting a significant number of patients. Here we test whether tumor hypoxia might commonly produce ER-α loss...
March 20, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28320300/chronic-alcohol-intoxication-is-not-accompanied-by-an-increase-in-calpain-proteolytic-activity-in-cardiac-muscle-of-rats
#17
Yu V Gritsyna, N N Salmov, A G Bobylev, I S Fadeeva, N I Fesenko, D G Sadikova, N I Kukushkin, Z A Podlubnaya, I M Vikhlyantsev
Enzymatic activity of Ca2+-dependent calpain proteases as well as the content and gene expression of μ-calpain (activated by micromolar calcium ion concentrations), calpastatin (inhibitor of calpains), and titin (substrate for calpains) were investigated in cardiac muscles of rats subjected to chronic alcoholization for 3 and 6 months. There was no increase in the "heart weight/body weight" parameter indicating development of heart hypertrophy in the alcoholized rats, while a decreasing trend was observed for this parameter in the rats after 6-month modeling of alcoholic cardiomyopathy, which indicated development of atrophic changes in the myocardium...
February 2017: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/28320298/sodium-orthovanadate-inhibits-proliferation-and-triggers-apoptosis-in-oral-squamous-cell-carcinoma-in-vitro
#18
A A Khalil, M J Jameson
Sodium orthovanadate (SOV) is a general inhibitor of tyrosine phosphatases, a large family of enzymes that catalyze the removal of phosphate groups from tyrosine residues. SOV is commonly used in the laboratory to preserve the protein tyrosyl phosphorylation state of proteins under study. It has shown promising antineoplastic activity in some human cancer cell lines; this effect has not been fully investigated in head and neck squamous cell carcinoma. In this study, the effect of SOV on cell growth, proliferation, viability, and apoptosis was assessed in Cal27 cells, an oral squamous cell carcinoma (OSCC) cell line...
February 2017: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/28319136/structural-insights-into-the-regulation-of-bacillus-subtilis-sigw-activity-by-anti-sigma-rsiw
#19
Shankar Raj Devkota, Eunju Kwon, Sung Chul Ha, Hyeun Wook Chang, Dong Young Kim
Bacillus subtilis SigW is localized to the cell membrane and is inactivated by the tight interaction with anti-sigma RsiW under normal growth conditions. Whereas SigW is discharged from RsiW binding and thus initiates the transcription of its regulon under diverse stress conditions such as antibiotics and alkaline shock. The release and activation of SigW in response to extracytoplasmic signals is induced by the regulated intramembrane proteolysis of RsiW. As a ZAS (Zinc-containing anti-sigma) family protein, RsiW has a CHCC zinc binding motif, which implies that its anti-sigma activity may be regulated by the state of zinc coordination in addition to the proteolytic cleavage of RsiW...
2017: PloS One
https://www.readbyqxmd.com/read/28319092/the-tdh-gcn5l1-fbxo15-kbp-axis-limits-mitochondrial-biogenesis-in-mouse-embryonic-stem%C3%A2-cells
#20
Valerio Donato, Massimo Bonora, Daniele Simoneschi, Davide Sartini, Yasusei Kudo, Anita Saraf, Laurence Florens, Michael P Washburn, Matthias Stadtfeld, Paolo Pinton, Michele Pagano
Self-renewing naive mouse embryonic stem cells (mESCs) contain few mitochondria, which increase in number and volume at the onset of differentiation. KBP (encoded by Kif1bp) is an interactor of the mitochondrial-associated kinesin Kif1Bα. We found that TDH, responsible for mitochondrial production of acetyl-CoA in mESCs, and the acetyltransferase GCN5L1 cooperate to acetylate Lys501 in KBP, allowing its recognition by and degradation via Fbxo15, an F-box protein transcriptionally controlled by the pluripotency core factors and repressed following differentiation...
March 20, 2017: Nature Cell Biology
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