المؤلفون: Justin E. Miller, Roger Castells-Graells, Mark A. Arbing, Aldo Munoz, Yi-Xiao Jiang, Charlize T. Espinoza, Brian Nguyen, Paul Moroz, Todd O. Yeates

المصدر: Biomolecules; Volume 13; Issue 7; Pages: 1122

مصطلحات موضوعية: protein design, beta-2 microglobulin (B2M), amyloidosis, dialysis, middle molecules, protein cages, nanoparticles

جغرافية الموضوع: agris

الوصف: Beta-2 microglobulin (B2M) is an immune system protein that is found on the surface of all nucleated human cells. B2M is naturally shed from cell surfaces into the plasma, followed by renal excretion. In patients with impaired renal function, B2M will accumulate in organs and tissues leading to significantly reduced life expectancy and quality of life. While current hemodialysis methods have been successful in managing electrolyte as well as small and large molecule disturbances arising in chronic renal failure, they have shown only modest success in managing plasma levels of B2M and similar sized proteins, while sparing important proteins such as albumin. We describe a systematic protein design effort aimed at adding the ability to selectively remove specific, undesired waste proteins such as B2M from the plasma of chronic renal failure patients. A novel nanoparticle built using a tetrahedral protein assembly as a scaffold that presents 12 copies of a B2M-binding nanobody is described. The designed nanoparticle binds specifically to B2M through protein–protein interactions with nanomolar binding affinity (~4.2 nM). Notably, binding to the nanoparticle increases the effective size of B2M by over 50-fold, offering a potential selective avenue for separation based on size. We present data to support the potential utility of such a nanoparticle for removing B2M from plasma by either size-based filtration or by polyvalent binding to a stationary matrix under blood flow conditions. Such applications could address current shortcomings in the management of problematic mid-sized proteins in chronic renal failure patients.

وصف الملف: application/pdf

العلاقة: Biomacromolecules: Proteins; https://dx.doi.org/10.3390/biom13071122Test

الإتاحة: https://doi.org/10.3390/biom13071122Test

المؤلفون: Nikolas Rapp, Pieter Evenepoel, Peter Stenvinkel, Leon Schurgers

المصدر: Toxins; Volume 12; Issue 10; Pages: 624

مصطلحات موضوعية: uremic toxins, uremia, chronic kidney disease, cardiovascular disease, vascular smooth muscle cells, vascular calcification, middle molecules, protein bound uremic solutes, water-soluble uremic solutes

جغرافية الموضوع: agris

الوصف: The cardiorenal syndrome relates to the detrimental interplay between the vascular system and the kidney. The uremic milieu induced by reduced kidney function alters the phenotype of vascular smooth muscle cells (VSMC) and promotes vascular calcification, a condition which is strongly linked to cardiovascular morbidity and mortality. Biological mechanisms involved include generation of reactive oxygen species, inflammation and accelerated senescence. A better understanding of the vasotoxic effects of uremic retention molecules may reveal novel avenues to reduce vascular calcification in CKD. The present review aims to present a state of the art on the role of uremic toxins in pathogenesis of vascular calcification. Evidence, so far, is fragmentary and limited with only a few uremic toxins being investigated, often by a single group of investigators. Experimental heterogeneity furthermore hampers comparison. There is a clear need for a concerted action harmonizing and standardizing experimental protocols and combining efforts of basic and clinical researchers to solve the complex puzzle of uremic vascular calcification.

وصف الملف: application/pdf

العلاقة: Uremic Toxins; https://dx.doi.org/10.3390/toxins12100624Test

الإتاحة: https://doi.org/10.3390/toxins12100624Test

المؤلفون: Raymond Vanholder, Anneleen Pletinck, Eva Schepers, Griet Glorieux

المصدر: Toxins; Volume 10; Issue 1; Pages: 33

مصطلحات موضوعية: uremic toxins, uremic toxicity, uremia, Chronic Kidney Disease, CKD, cardiovascular disease, inflammation, fibrosis, patho-physiology CKD, middle molecules, protein bound uremic solutes, water-soluble uremic solutes

جغرافية الموضوع: agris

الوصف: In this narrative review, the biological/biochemical impact (toxicity) of a large array of known individual uremic retention solutes and groups of solutes is summarized. We classified these compounds along their physico-chemical characteristics as small water-soluble compounds or groups, protein bound compounds and middle molecules. All but one solute (glomerulopressin) affected at least one mechanism with the potential to contribute to the uremic syndrome. In general, several mechanisms were influenced for each individual solute or group of solutes, with some impacting up to 7 different biological systems of the 11 considered. The inflammatory, cardio-vascular and fibrogenic systems were those most frequently affected and they are one by one major actors in the high morbidity and mortality of CKD but also the mechanisms that have most frequently been studied. A scoring system was built with the intention to classify the reviewed compounds according to the experimental evidence of their toxicity (number of systems affected) and overall experimental and clinical evidence. Among the highest globally scoring solutes were 3 small water-soluble compounds [asymmetric dimethylarginine (ADMA); trimethylamine-N-oxide (TMAO); uric acid], 6 protein bound compounds or groups of protein bound compounds [advanced glycation end products (AGEs); p-cresyl sulfate; indoxyl sulfate; indole acetic acid; the kynurenines; phenyl acetic acid;] and 3 middle molecules [β2-microglobulin; ghrelin; parathyroid hormone). In general, more experimental data were provided for the protein bound molecules but for almost half of them clinical evidence was missing in spite of robust experimental data. The picture emanating is one of a complex disorder, where multiple factors contribute to a multisystem complication profile, so that it seems of not much use to pursue a decrease of concentration of a single compound.

وصف الملف: application/pdf

العلاقة: Uremic Toxins; https://dx.doi.org/10.3390/toxins10010033Test

الإتاحة: https://doi.org/10.3390/toxins10010033Test