scholarly journals Uremic Toxins Affecting Cardiovascular Calcification: A Systematic Review

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2428
Author(s):  
Jana Holmar ◽  
Sofia de la Puente-Secades ◽  
Jürgen Floege ◽  
Heidi Noels ◽  
Joachim Jankowski ◽  
...  
Keyword(s):  
Animal Studies ◽  
Inhibitory Effect ◽  
Uremic Toxins ◽  
Uremic Toxin ◽  
Symmetric Dimethylarginine ◽  
Post Translational Modifications ◽  
Regulatory Effects ◽  
The Impact ◽  
Guanidinosuccinic Acid

Cardiovascular calcification is highly prevalent and associated with increased morbidity in chronic kidney disease (CKD). This review examines the impact of uremic toxins, which accumulate in CKD due to a failing kidney function, on cardiovascular calcification. A systematic literature search identified 41 uremic toxins that have been studied in relation to cardiovascular calcification. For 29 substances, a potentially causal role in cardiovascular calcification was addressed in in vitro or animal studies. A calcification-inducing effect was revealed for 16 substances, whereas for three uremic toxins, namely the guanidino compounds asymmetric and symmetric dimethylarginine, as well as guanidinosuccinic acid, a calcification inhibitory effect was identified in vitro. At a mechanistic level, effects of uremic toxins on calcification could be linked to the induction of inflammation or oxidative stress, smooth muscle cell osteogenic transdifferentiation and/or apoptosis, or alkaline phosphatase activity. For all middle molecular weight and protein-bound uremic toxins that were found to affect cardiovascular calcification, an increasing effect on calcification was revealed, supporting the need to focus on an increased removal efficiency of these uremic toxin classes in dialysis. In conclusion, of all uremic toxins studied with respect to calcification regulatory effects to date, more uremic toxins promote rather than reduce cardiovascular calcification processes. Additionally, it highlights that only a relatively small part of uremic toxins has been screened for effects on calcification, supporting further investigation of uremic toxins, as well as of associated post-translational modifications, on cardiovascular calcification processes.

scholarly journals Investigating crosstalk among PTMs provides novel insight into the structural basis underlying the differential effects of Nt17 PTMs on mutant Httex1 aggregation

2021 ◽  
Author(s):  
Anass Chiki ◽  
Zhidian Zhang ◽  
Kolla Rajasekhar ◽  
Luciano A. Abriata ◽  
Iman Rostami ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Helical Conformation ◽  
Structural Basis ◽  
Similar Distribution ◽  
Post Translational Modifications ◽  
Differential Effects ◽  
The Impact ◽  
Insight Into

AbstractPost-translational modifications (PTMs) within the first 17 amino acids (Nt17) of the Huntingtin protein (Htt) have been shown to inhibit the aggregation and attenuate the toxicity of mutant Htt proteins in vitro and in various models of Huntington’s disease. Our group’s previous studies suggested that the Nt17 PTM code is a combinatorial code that involves a complex interplay between different PTMs. Here, we expand on these studies by investigating the effect of methionine 8 oxidation (oxM8) and crosstalk between this PTM and either lysine 6 acetylation (AcK6) or threonine 3 phosphorylation (pT3) on the aggregation of mutant Httex1. We show that M8 oxidation delays but does not inhibit the aggregation and has no effect on the final morphologies of mutant Httex1 aggregates. This delay in aggregation kinetics could be attributed to the transient accumulation of oligomeric aggregates, which disappear upon the formation of Httex1 oxM8 fibrils. Interestingly, the presence of both oxM8 and AcK6 resulted in dramatic inhibition of Httex1 fibrillization, whereas the presence of oxM8 did not influence the aggregation inhibitory effect of pT3. To gain insight into the structural basis underlying these proteins’ aggregation properties, we investigated the impact of each PTM and the combination of these PTMs on the conformational properties of the Nt17 peptide by circular dichroism spectroscopy and molecular dynamics simulation. These studies show that M8 oxidation decreases the helicity of the Nt17 in the presence or absence of PTMs and provides novel insight into the structural basis underlying the effects of different PTMs on mutant Httex1 aggregation. PTMs that lower the mutant Httex1 aggregation rate (oxM8, AcK6/oxM8, pT3, pT3/oxM8, and phosphorylation at Serine 13) result in stabilization and increased population of a short N-terminal helix (first eight residues) in Nt17 or decreased abundance of other helical forms, including long helix and short C-terminal helix. PTMs that did not alter the aggregation of mutant Httex1 exhibit a similar distribution of helical conformation as the unmodified peptides. These results show that the relative abundance of N- vs. C-terminal helical conformations and long helices, rather than the overall helicity of Nt17, better explains the effect of different Nt17 PTMs on mutant Httex1; thus, explaining the lack of correlation between the effect of PTMs on the overall helicity of Nt17 and mutant Httex1 aggregation in vitro. Taken together, our results provide novel structural insight into the differential effects of single PTMs and crosstalk between different PTMs in regulating mutant Httex1 aggregation.TOC Figure

scholarly journals A history of uremic toxicity and of the European Uremic Toxin Work Group (EUTox)

2021 ◽  
Author(s):  
Raymond Vanholder ◽  
Angel Argiles ◽  
Joachim Jankowski ◽  
Keyword(s):  
Work Group ◽  
Target Identification ◽  
Kidney Injury ◽  
Uremic Toxins ◽  
Uremic Toxin ◽  
Post Translational Modifications ◽  
History Of ◽  
Advanced Stages ◽  
Uremic Syndrome

Abstract The uremic syndrome is a complex clinical picture developing in the advanced stages of chronic kidney disease (CKD) resulting in a myriad of complications and a high early mortality. This picture is to a significant extent defined by retention of metabolites and peptides that with a preserved kidney function are excreted or degraded by the kidneys. In as far as those solutes have a negative biological/biochemical impact, they are called uremic toxins. Here, we describe the historical evolution of the scientific knowledge about uremic toxins and the role played in this process by the European Uremic Toxin Work Group (EUTox) during the last two decades. The earliest knowledge about a uremic toxin goes back to the early 17th century when the existence of what later would appear to be urea was recognized. It cost about two further centuries to better define the role of urea and its link to kidney failure and one more century to identify the relevance of post-translational modifications caused by urea such as carbamoylation. The knowledge progressively extended, especially from 1980 on, by the identification of more and more toxins and their adverse biological/biochemical impact. Progress of knowledge was paralleled and impacted by evolution of dialysis strategies. The last two decades, when Insights grew exponentially, coincides with the foundation and activity of EUTox. In the final section we summarize the role and accomplishments of EUTox and the part it is likely to play in future action, which should be organized around focus points like biomarker and potential target identification, intestinal generation, toxicity mechanisms and their correction, kidney and extracorporeal removal, patient-oriented outcomes, and toxin characteristics in acute kidney injury and transplantation.

scholarly journals A green tea polyphenol Epigallocatechin-3-gallate modulates Tau Post-translational modifications and cytoskeletal network

2020 ◽  
Author(s):  
Shweta Kishor Sonawane ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Green Tea ◽  
Advanced Glycation Endproducts ◽  
Neuroblastoma Cells ◽  
Tea Polyphenol ◽  
Advanced Glycation ◽  
Microtubule Organizing Center ◽  
Post Translational Modifications ◽  
Green Tea Polyphenol ◽  
The Impact

AbstractBackgroundAlzheimer’s disease is a type of dementia denoted by progressive neuronal death due to the accumulation of proteinaceous aggregates of Tau. Post-translational modifications like hyperphosphorylation, truncation, glycation, etc. play a pivotal role in Tau pathogenesis. Glycation of Tau aids in paired helical filament formation and abates its microtubule-binding function. The chemical modulators of Tau PTMs, such as kinase inhibitors and antibody-based therapeutics, have been developed, but natural compounds, as modulators of Tau PTMs are not much explored.MethodsWe applied biophysical and biophysical techniques like fluorescence kinetics, SDS-PAGE, western blot analysis and transmission electron microscopy to investigate the impact of EGCG on Tau glycation in vitro. The effect of glycation on cytoskeleton instability and its EGCG-mediated rescue were studied by immunofluorescence in neuroblastoma cells.ResultsEGCG inhibited methyl glyoxal (MG)-induced Tau glycation in vitro. EGCG potently inhibited MG-induced advanced glycation endproducts formation in neuroblastoma cells as well modulated the localization of AT100 phosphorylated Tau in the cells. In addition to preventing the glycation, EGCG enhanced actin-rich neuritic extensions and rescued actin and tubulin cytoskeleton severely disrupted by MG. EGCG maintained the integrity of the Microtubule Organizing Center (MTOC) stabilized microtubules by Microtubule-associated protein RP/EB family member 1 (EB1).ConclusionsWe report EGCG, a green tea polyphenol, as a modulator of in vitro methylglyoxal-induced Tau glycation and its impact on reducing advanced glycation end products in neuroblastoma cells. We unravel unprecedented function of EGCG in remodeling neuronal cytoskeletal integrity.

The application of Ussing chambers for determining the impact of microbes and probiotics on intestinal ion transport

2013 ◽  
Vol 91 (9) ◽  
pp. 663-670 ◽  
Author(s):  
Kevin W. Lomasney ◽  
Niall P. Hyland
Keyword(s):  
Ion Transport ◽  
Animal Studies ◽  
Ussing Chamber ◽  
Positive Influence ◽  
Mechanisms Of Action ◽  
Ussing Chambers ◽  
Host Microbe Interactions ◽  
The Impact ◽  
Intestinal Ion Transport

Host–microbe interactions have gained considerable attention in recent years with regards to their role in various organic disorders and diseases. In particular, research efforts have focused on the intestinal microbiota, where the largest and most diverse populations not only co-exist with the host, but also directly influence the state and function of the gastrointestinal (GI) tract. Moreover, both human and animal studies alike are now beginning to show a positive influence of probiotic bacteria on GI disorders associated with diarrhoea or constipation. Diarrheagenic GI diseases, such as those caused by Vibreo cholera or enterpathogenic Eschericia coli, have well-characterised interactions with the host that explain much of the observed symptoms, in particular severe diarrhoea. However, the mechanisms of action of nonpathogenic bacteria or probiotics on host physiology are less clearly understood. In the context of defining the mechanisms of action of probiotics in vitro, the Ussing chamber has proven to be a particularly useful tool. Here, we will present data from several studies that have defined molecular targets for microbes and putative probiotics in the regulation of intestinal secretory and absorptive function, and we will discuss these in the context of their application in pathogen- or inflammation-induced alterations in intestinal ion transport.

scholarly journals The Impact of Uremic Toxins on Cerebrovascular and Cognitive Disorders

Toxins ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 303 ◽  
Author(s):  
Maryam Assem ◽  
Mathilde Lando ◽  
Maria Grissi ◽  
Saïd Kamel ◽  
Ziad Massy ◽  
...  
Keyword(s):  
Animal Experiments ◽  
Cognitive Disorders ◽  
Neurological Complications ◽  
Cerebrovascular Diseases ◽  
Uremic Toxins ◽  
Current Evidence ◽  
Cognitive Disorders And Dementia ◽  
The Impact

Individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing cognitive disorders and dementia. Stroke is also highly prevalent in this population and is associated with a higher risk of neurological deterioration, in-hospital mortality, and poor functional outcomes. Evidence from in vitro studies and in vivo animal experiments suggests that accumulation of uremic toxins may contribute to the pathogenesis of stroke and amplify vascular damage, leading to cognitive disorders and dementia. This review summarizes current evidence on the mechanisms by which uremic toxins may favour the occurrence of cerebrovascular diseases and neurological complications in CKD.

scholarly journals A Bifunctional Adsorber Particle for the Removal of Hydrophobic Uremic Toxins from Whole Blood of Renal Failure Patients

Toxins ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 389 ◽  
Author(s):  
Marieke Sternkopf ◽  
Sven Thoröe-Boveleth ◽  
Tobias Beck ◽  
Kirsten Oleschko ◽  
Ansgar Erlenkötter ◽  
...  
Keyword(s):  
Adsorption Capacity ◽  
Binding Affinity ◽  
Whole Blood ◽  
Uremic Toxins ◽  
In Vivo Studies ◽  
Uremic Toxin ◽  
High Binding ◽  
High Binding Affinity

Hydrophobic uremic toxins accumulate in patients with chronic kidney disease, contributing to a highly increased cardiovascular risk. The clearance of these uremic toxins using current hemodialysis techniques is limited due to their hydrophobicity and their high binding affinity to plasma proteins. Adsorber techniques may be an appropriate alternative to increase hydrophobic uremic toxin removal. We developed an extracorporeal, whole-blood bifunctional adsorber particle consisting of a porous, activated charcoal core with a hydrophilic polyvinylpyrrolidone surface coating. The adsorption capacity was quantified using analytical chromatography after perfusion of the particles with an albumin solution or blood, each containing mixtures of hydrophobic uremic toxins. A time-dependent increase in hydrophobic uremic toxin adsorption was depicted and all toxins showed a high binding affinity to the adsorber particles. Further, the particle showed a sufficient hemocompatibility without significant effects on complement component 5a, thrombin-antithrombin III complex, or thrombocyte concentration in blood in vitro, although leukocyte counts were slightly reduced. In conclusion, the bifunctional adsorber particle with cross-linked polyvinylpyrrolidone coating showed a high adsorption capacity without adverse effects on hemocompatibility in vitro. Thus, it may be an interesting candidate for further in vivo studies with the aim to increase the efficiency of conventional dialysis techniques.

Vitamin C inhibits the activation of the NLRP3 inflammasome by scavenging mitochondrial ROS

Inflammasome ◽  
2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Xuesong Sang ◽  
Hongbin Wang ◽  
Yihui Chen ◽  
Qiuhong Guo ◽  
Ailing Lu ◽  
...  
Keyword(s):  
Vitamin C ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Protein Complexes ◽  
Inhibitory Effect ◽  
Inflammasome Activation ◽  
Mitochondrial Ros ◽  
Regulatory Effects

AbstractInflammasomes are intracellular protein complexes that mediate maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18. Inflammasomes have been connected with various diseases, therefore the regulation of inflammasome activation is important for the development of novel therapies for many inflammatory syndromes. Vitamin C is an essential nutrient and has regulatory effects on immune cells. Here we report that vitamin C has an inhibitory effect on the activation of the NLRP3 inflammasome in vitro and in vivo. Mechanistically, this inhibition is through scavenging mitochondrial ROS but not through NF-κB inhibition. Moreover, specificity tests show that the AIM2 inflammasome and the NLRC4 inflammasome can also be inhibited by vitamin C. Our results have thus identified a new inflammasome regulator and provide therapeutic potential for inflammasome-associated diseases.

scholarly journals Advanced oxidation protein products downregulate CYP1A2 and CYP3A4 expression and activity via the NF-κB-mediated signaling pathway in vitro and in vivo

2021 ◽  
Author(s):  
Tianrong Xun ◽  
Zhufen Lin ◽  
Xiaokang Wang ◽  
Xia Zhan ◽  
Haixing Feng ◽  
...  
Keyword(s):  
Liver Microsomes ◽  
Advanced Oxidation ◽  
Uremic Toxins ◽  
Uremic Toxin ◽  
Dependent Manner ◽  
Advanced Oxidation Protein Products ◽  
Protein Levels ◽  
Cyp3a4 Expression

AbstractUremic toxin accumulation is one possible reason for alterations in hepatic drug metabolism in patients with chronic kidney disease (CKD). However, the types of uremic toxins and underlying mechanisms are poorly understood. In this study, we report the role of advanced oxidation protein products (AOPPs), a modified protein uremic toxin, in the downregulation of cytochromes P450 1A2 (CYP1A2) and P450 3A4 (CYP3A4) expression levels and activities. We found that AOPP accumulation in plasma in a rat CKD model was associated with decreased protein levels of CYP1A2 and CYP3A4. CYP1A2 and CYP3A4 metabolites (acetaminophen and 6β-hydroxytestosterone, respectively,) in liver microsomes were also significantly decreased. In human hepatocytes, AOPPs significantly decreased CYP1A2 and CYP3A4 protein levels in a dose- and time-dependent manner and downregulated their activities; however, bovine serum albumin (BSA), a synthetic precursor of AOPPs, had no effect on these parameters. The effect of AOPPs was associated with upregulation of p-IKKα/β, p-IκBα, p-NF-κB, and inflammatory cytokines protein levels and increases in p-IKKα/β/IKKα, p-IκBα/IκBα, and p-NF-κB/NF-κB phosphorylation ratios. Further, NF-kB pathway inhibitors BAY-117082 and PDTC abolished the downregulatory effects of AOPPs. These findings suggest that AOPPs downregulate CYP1A2 and CYP3A4 expression and activities by increasing inflammatory cytokine production and stimulating NF-κB-mediated signaling. Protein uremic toxins, such as AOPPs, may modify the nonrenal clearance of drugs in patients with CKD by influencing metabolic enzymes.

scholarly journals Group IVA Cytosolic Phospholipase A2Regulates the G2-to-M Transition by Modulating the Activity of Tumor Suppressor SIRT2

2015 ◽  
Vol 35 (21) ◽  
pp. 3768-3784 ◽  
Author(s):  
Said Movahedi Naini ◽  
Alice M. Sheridan ◽  
Thomas Force ◽  
Jagesh V. Shah ◽  
Joseph V. Bonventre
Keyword(s):  
Tumor Suppressor ◽  
Cyclin A ◽  
Inhibitory Effect ◽  
Mitotic Entry ◽  
Cytosolic Phospholipase ◽  
Age Related ◽  
Group Iva ◽  
The Impact

The G2-to-M transition (or prophase) checkpoint of the cell cycle is a critical regulator of mitotic entry. SIRT2, a tumor suppressor gene, contributes to the control of this checkpoint by blocking mitotic entry under cellular stress. However, the mechanism underlying both SIRT2 activation and regulation of the G2-to-M transition remains largely unknown. Here, we report the formation of a multiprotein complex at the G2-to-M transitionin vitroandin vivo. Group IVA cytosolic phospholipase A2(cPLA2α) acts as a bridge in this complex to promote binding of SIRT2 to cyclin A-Cdk2. Cyclin A-Cdk2 then phosphorylates SIRT2 at Ser331. This phosphorylation reduces SIRT2 catalytic activity and its binding affinity to centrosomes and mitotic spindles, promoting G2-to-M transition. We show that the inhibitory effect of cPLA2α on SIRT2 activity impacts various cellular processes, including cellular levels of histone H4 acetylated at K16 (Ac-H4K16) and Ac-α-tubulin. This regulatory effect of cPLA2α on SIRT2 defines a novel function of cPLA2α independent of its phospholipase activity and may have implications for the impact of SIRT2-related effects on tumorigenesis and age-related diseases.

scholarly journals Distribution and vulnerability of transcriptional outputs across the genome in Myc-amplified medulloblastoma cells

2021 ◽  
Author(s):  
Rui Yang ◽  
Wenzhe Wang ◽  
Meichen Dong ◽  
Kristen Roso ◽  
Paula Greer ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Target Genes ◽  
De Novo ◽  
Inhibitory Effect ◽  
Nucleotide Synthesis ◽  
High Level ◽  
The Impact

Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes1-4. While it is well established that Myc functions by binding to its target genes to regulate their transcription5, the distribution of the transcriptional output across the human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals that a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructure, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly only in genes involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on infrastructure genes, which was accompanied by the abrogation of MB cells proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, provide new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in cancer cells empowered by a high level of Myc oncoprotein.

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