Vasilios Devetzis, Arezoo Daryadel, Stefanos Roumeliotis, Marios Theodoridis, Carsten A Wagner, Stefan Hettwer, Uyen Huynh-Do, Passadakis Ploumis, Spyridon Arampatzis
BACKGROUND: Diabetes is the leading cause of CKD in the developed world. C-terminal fragment of agrin (CAF) is a novel kidney function and injury biomarker. We investigated whether serum CAF predicts progression of kidney disease in type 2 diabetics. METHODS: Serum CAF levels were measured in 71 elderly patients with diabetic nephropathy using a newly developed commercial ELISA kit (Neurotune®). Estimated glomerular filtration rate (eGFR) and proteinuria in spot urine were assessed at baseline and after 12 months follow up...
2015: PloS One
I Bondoc, S K Cochrane, T S Church, P Dahinden, S Hettwer, F-C Hsu, R S Stafford, M Pahor, T W Buford
OBJECTIVES: C-terminal Agrin Fragment (CAF) has been proposed as a potential circulating biomarker for predicting changes in physical function among older adults. To determine the effect of a one-year PA intervention on changes in CAF concentrations and to evaluate baseline and longitudinal associations between CAF concentrations and indices of physical function. DESIGN: Ancillary study to the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P), a multi-site randomized clinical trial designed to evaluate the effects of chronic exercise on the physical function of older adults at risk for mobility disability...
November 2015: Journal of Nutrition, Health & Aging
Lisa Steinbeck, Nicole Ebner, Miroslava Valentova, Tarek Bekfani, Sebastian Elsner, Pius Dahinden, Stefan Hettwer, Nadja Scherbakov, Jörg C Schefold, Anja Sandek, Jochen Springer, Wolfram Doehner, Stefan D Anker, Stephan von Haehling
AIMS: Skeletal muscle wasting affects 20% of patients with chronic heart failure and has serious implications for their activities of daily living. Assessment of muscle wasting is technically challenging. C-terminal agrin-fragment (CAF), a breakdown product of the synaptically located protein agrin, has shown early promise as biomarker of muscle wasting. We sought to investigate the diagnostic properties of CAF in muscle wasting among patients with heart failure. METHODS AND RESULTS: We assessed serum CAF levels in 196 patients who participated in the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF)...
December 2015: European Journal of Heart Failure
Dominik Steubl, Anna Vogel, Stefan Hettwer, Susanne Tholen, Peter B Luppa, Ina-Christine Rondak, Lutz Renders, Uwe Heemann, Marcel Roos
BACKGROUND: C-terminal agrin fragment (CAF), cleavage product of agrin, was previously correlated with kidney function in renal transplant patients. This article studies the predictive value of CAF for long-term outcomes in renal transplant recipients. METHODS: In this observational cohort study, serum CAF, creatinine and blood-urea-nitrogen (BUN) concentrations and eGFR (CKD-EPI) were assessed 1-3 months after transplantation in 105 patients undergoing kidney transplantation...
January 2016: Clinical Chemistry and Laboratory Medicine: CCLM
Alexander Kalinkovich, Gregory Livshits
Sarcopenia, an age-related decline in skeletal muscle mass and function, dramatically affects the life quality of elder people. In view of increasing life expectancy, sarcopenia renders a heavy burden on the health care system. However, although there is a consensus that sarcopenia is a multifactorial syndrome, its etiology, underlying mechanisms, and even definition remain poorly delineated, thus, preventing development of a precise treatment strategy. The main aim of our review is to critically analyze potential sarcopenia biomarkers in light of the molecular mechanisms of their involvement in sarcopenia pathogenesis...
July 2015: Ageing Research Reviews
Michael Drey, Michael Behnes, Robert Kob, Dominic Lepiorz, Stefan Hettwer, Cornelius Bollheimer, Cornel C Sieber, Thomas Bertsch, Ursula Hoffmann
BACKGROUND: One of the main causes of acute kidney injury (AKI) in patients treated on an intensive care unit (ICU) is sepsis. The identification of new biomarkers indicating the early development and future course of AKI are of utmost medical interest. The C-terminal agrin fragment (CAF) is measurable in blood serum and might reflect kidney function. Therefore, this study evaluates CAF in patients presenting to an internal ICU with severe sepsis or septic shock. Serum levels of CAF are correlated with biomarkers of kidney function, markers of systemic inflammation, and the presence of AKI and renal replacement therapy (RRT)...
2015: Clinical Laboratory
Dominik Steubl, Stefan Hettwer, Pius Dahinden, Peter Luppa, Ina-Christine Rondak, Claudia Regenbogen, Konrad F Stock, Lutz Renders, Uwe Heemann, Marcel Roos
BACKGROUND: C-terminal agrin fragment (CAF, size 22 kDa) is a promising new biomarker for kidney function. This study evaluated the usefulness of CAF as a serum biomarker for residual renal function (RRF) in patients undergoing automated peritoneal dialysis (APD). PATIENTS AND METHODS: Serum, urine and dialysate samples were obtained in 12 end-stage renal disease patients undergoing APD. Total, renal and peritoneal clearances were calculated for CAF, creatinine, blood urea nitrogen (BUN) and cystatin c...
February 2015: International Urology and Nephrology
Emanuele Marzetti, Riccardo Calvani, Maria Lorenzi, Federico Marini, Emanuela D'Angelo, Anna Maria Martone, Michela Celi, Matteo Tosato, Roberto Bernabei, Francesco Landi
BACKGROUND: Serum concentrations of the C-terminal fragment of agrin (CAF), a component of the neuromuscular junction (NMJ), are elevated in older community-dwellers with sarcopenia. Whether CAF may be used as a marker for muscle wasting in the presence of NMJ mechanical damage is presently unknown. The present study was undertaken to verify if serum CAF levels were associated with sarcopenia in older hip fractured patients. METHODS: Analyses were conducted in older adults hospitalized for traumatic hip fracture...
December 2014: Experimental Gerontology
Jeffrey R Stout, Maren S Fragala, Jay R Hoffman, Edward H Robinson, William P Mccormack, Jeremy R Townsend, Adam R Jatjner, Nadia S Emerson, Leonardo P Oliveira, David H Fukuda
INTRODUCTION: The aim of this study was to examine the relationship between serum C-terminal agrin fragment (CAF) concentrations and neuromuscular fatigue in older adults. METHODS: Twenty-two healthy older men and women volunteered for this study. Resting fasted blood samples were collected and prepared for measurement of serum CAF concentration by a commercially available ELISA kit. The onset of neuromuscular fatigue was measured by monitoring electromyographic fatigue curves from the vastus lateralis muscle using the physical working capacity at fatigue threshold (PWCFT ) test...
January 2015: Muscle & Nerve
Dominik Steubl, Stefan Hettwer, Pius Dahinden, Petra Wolf, Peter Luppa, Carsten A Wagner, Claudius Küchle, Christoph Schmaderer, Lutz Renders, Uwe Heemann, Marcel Roos
C-terminal agrin fragment (CAF, 22 kDa) has been shown to be a promising new rapid biomarker for kidney function. This study evaluated the influence of hemodialysis (HD) and hemodiafiltration (HDF) treatment on serum CAF concentrations in patients with end-stage renal disease (ESRD). A total of 36 patients with ESRD undergoing chronic HD/HDF treatment were enrolled (21 high-flux-HD/Fx60 membrane, 7 high-flux-HD/Elisio19H membrane, and 8 HDF/Elisio19H membrane). On a midweek session, blood samples were obtained before, at halftime, and post-treatment...
November 2014: Translational Research: the Journal of Laboratory and Clinical Medicine
Dominik Steubl, Stefan Hettwer, Wim Vrijbloed, Pius Dahinden, Petra Wolf, Peter Luppa, Carsten A Wagner, Lutz Renders, Uwe Heemann, Marcel Roos
BACKGROUND: The C-terminal agrin fragment (CAF) is a cleavage product of agrin, the major proteoglycan of the glomerular basement membrane. This article studies if CAF could serve as a biomarker for renal function in renal transplant recipients. MATERIAL AND METHODS: We measured serum CAF and creatinine concentrations and calculated estimated glomerular filtration rate (eGFR) (MDRD) in 96 healthy individuals and in 110 end-stage renal disease patients undergoing kidney transplantation before and after transplantation...
2013: American Journal of Nephrology
Maren S Fragala, Adam R Jajtner, Kyle S Beyer, Jeremy R Townsend, Nadia S Emerson, Tyler C Scanlon, Leonardo P Oliveira, Jay R Hoffman, Jeffrey R Stout
BACKGROUND: N-terminal peptide of procollagen type III (P3NP) and C-terminal agrin fragment (CAF) are circulating biomarkers that are related to lean body mass in older adults. P3NP is a circulating marker reflective of muscular structural remodeling while CAF is a circulating marker of neuromuscular remodeling. As resistance exercise is an established intervention that can effectively improve muscle quality, we sought to evaluate circulating biomarker changes corresponding to a resistance exercise intervention in older adults...
June 2014: Journal of Cachexia, Sarcopenia and Muscle
Claudio Gisler, Daniel Lüscher, Philipp Schätzle, Stephanie Dürr, Antonio Baici, Giovanna Galliciotti, Raymond Reif, Marc F Bolliger, Beat Kunz, Peter Sonderegger
The serine peptidase neurotrypsin is stored in presynaptic nerve endings and secreted in an inactive zymogenic form by synaptic activity. After activation, which requires activity of postsynaptic NMDA (N-methyl-D-aspartate) receptors, neurotrypsin cleaves the heparan sulfate proteoglycan agrin at active synapses. The resulting C-terminal 22-kDa fragment of agrin induces dendritic filopodia, which are considered to be precursors of new synapses. In the present study, we investigated the role of GAGs (glycosaminoglycans) in the activation of neurotrypsin and neurotrypsin-dependent agrin cleavage...
July 1, 2013: Biochemical Journal
Trushar R Patel, Georgina Butler, Ainsley McFarlane, Irene Xie, Christopher M Overall, Jörg Stetefeld
BACKGROUND: Agrin is the key inducer of postsynaptic differentiations at the neuromuscular junction. The multidomain heparan sulfate proteoglycan is mediating via its N-terminal segment the interaction with laminin, whereas the C-terminal portion is responsible for Dystroglycan binding and clustering of the Acetylcholine receptor. Matrix metalloproteinases (MMP) are known to play essential roles in matrix remodeling, degradation and regulation of extracellular signaling networks. PRINCIPAL FINDINGS: Site-specific processing of Agrin provides key insight into regulatory effects of Matrix metalloproteinases (MMPs)...
2012: PloS One
M Drey, C C Sieber, J M Bauer, W Uter, P Dahinden, R G Fariello, J W Vrijbloed
INTRODUCTION: Sarcopenia is considered to be an enormous burden for both the individuals affected and for society at large. A multifactorial aetiology of this geriatric syndrome has been discussed. Amongst other pathomechanisms, the degeneration of the neuromuscular junction (NMJ) may be of major relevance. The intact balance between the pro-synaptic agent agrin and the anti-synaptic agent neurotrypsin ensures a structurally and functionally intact NMJ. Excessive cleavage of the native motoneuron-derived agrin by neurotrypsin into a C-terminal Agrin Fragment (CAF) leads to functional disintegration at the NMJ and may consecutively cause sarcopenia...
January 2013: Experimental Gerontology
Stefan Hettwer, Pius Dahinden, Stefan Kucsera, Carlo Farina, Shaheen Ahmed, Ruggero Fariello, Michael Drey, Cornel Christian Sieber, Jan Willem Vrijbloed
Sarcopenia is a recently defined medical condition described as age-associated loss of skeletal muscle mass and function. Recently, a transgenic mouse model was described linking dispersal of the neuromuscular junction caused by elevated agrin degradation to the rapid onset of sarcopenia. These mice show a significant elevation of serum levels of a C-terminal agrin fragment (CAF) compared to wild-type littermates. A series of experiments was designed to ascertain the significance of elevated agrin degradation in the development of human sarcopenia...
January 2013: Experimental Gerontology
Trushar R Patel, Markus Meier, Jianhua Li, Gordon Morris, Arthur J Rowe, Jörg Stetefeld
Agrin is a large heparin sulphate proteoglycan with multiple domains, which is located in the extracellular matrix. The C-terminal G3 domain of agrin is functionally one of the most important domains. It harbors an α-dystroglycan binding site and carries out acetylcholine receptor clustering activities. In the present study, we have fused the G3 domain of agrin to an IgG Fc domain to produce a G3-Fc fusion protein that we intend to use as a tool to investigate new binding partners of agrin. As a first step of the study, we have characterized the recombinant fusion protein using a multidisciplinary approach using dynamic light scattering, analytical ultracentrifugation and small angle X-ray scattering (SAXS)...
June 2011: Protein Science
Henning Tidow, Daniel Mattle, Poul Nissen
Agrin mediates accumulation of acetylcholine receptors (AChRs) at the developing neuromuscular junction, but has also been implicated as a regulator of central nervous system (CNS) synapses. A C-terminal region of agrin (Ag-C20) binds to the α3 subunit of the sodium-potassium ATPase (NKA) in CNS neurons suggesting that α3NKA is a neuronal agrin receptor, whereas a shorter agrin fragment (Ag-C15) was shown to act as a competitive antagonist. Here, we show that the agrin C22 construct, which represents the naturally occurring neurotrypsin cleavage product, constitutes a well-folded, stable domain, while the deletion of 48 residues that correspond to strands β1-β4 of the agrin laminin G3 domain imposed by the agrin C15 construct leads to a misfolded protein...
January 2011: Protein Engineering, Design & Selection: PEDS
László Bányai, Peter Sonderegger, László Patthy
The C-terminal 95 kDa fragment of some isoforms of vertebrate agrins is sufficient to induce clustering of acetylcholine receptors but despite two decades of intense agrin research very little is known about the function of the other isoforms and the function of the larger, N-terminal part of agrins that is common to all isoforms. Since the N-terminal part of agrins contains several follistatin-domains, a domain type that is frequently implicated in binding TGFbetas, we have explored the interaction of the N-terminal part of rat agrin (Agrin-Nterm) with members of the TGFbeta family using surface plasmon resonance spectroscopy and reporter assays...
2010: PloS One
Tobias Wolfram, Joachim P Spatz, Robert W Burgess
BACKGROUND: Molecular spacing is important for cell adhesion in a number of ways, ranging from the ordered arrangement of matrix polymers extracellularly, to steric hindrance of adhesion/signaling complexes intracellularly. This has been demonstrated using nanopatterned RGD peptides, a canonical extracellular matrix ligand for integrin interactions. Cell adhesion was greatly reduced when the RGD-coated nanoparticles were separated by more than 60 nm, indicating a sharp spacing-dependent threshold for this form of cell adhesion...
December 4, 2008: BMC Cell Biology
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