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Journal of the American Society of... Jul 2012An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621... (Comparative Study)
Comparative Study Review
An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articles most frequently reported concentrations of β2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations, although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD.
Topics: Chronic Disease; Homocysteine; Humans; Indican; Kidney Diseases; Parathyroid Hormone; Toxins, Biological; Uremia; Uric Acid; beta 2-Microglobulin
PubMed: 22626821
DOI: 10.1681/ASN.2011121175 -
Journal of Cellular and Molecular... Apr 2019Accumulating evidence has indicated that intestinal microbiota is involved in the development of various human diseases, including cardiovascular diseases (CVDs). In the... (Review)
Review
Accumulating evidence has indicated that intestinal microbiota is involved in the development of various human diseases, including cardiovascular diseases (CVDs). In the recent years, both human and animal experiments have revealed that alterations in the composition and function of intestinal flora, recognized as gut microflora dysbiosis, can accelerate the progression of CVDs. Moreover, intestinal flora metabolizes the diet ingested by the host into a series of metabolites, including trimethylamine N-oxide, short chain fatty acids, secondary bile acid and indoxyl sulfate, which affects the host physiological processes by activation of numerous signalling pathways. The aim of this review was to summarize the role of gut microbiota in the pathogenesis of CVDs, including coronary artery disease, hypertension and heart failure, which may provide valuable insights into potential therapeutic strategies for CVD that involve interfering with the composition, function and metabolites of the intestinal flora.
Topics: Bile Acids and Salts; Cardiovascular Diseases; Dysbiosis; Fatty Acids; Gastrointestinal Microbiome; Heart Failure; Humans; Hypertension; Indican; Methylamines; Probiotics; Signal Transduction
PubMed: 30712327
DOI: 10.1111/jcmm.14195 -
Nature Medicine Jun 2016Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to...
Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-β are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.
Topics: Animals; Astrocytes; Case-Control Studies; Cell Proliferation; Central Nervous System; Chemokine CCL2; Chromatin Immunoprecipitation; Chromatography, High Pressure Liquid; Encephalomyelitis, Autoimmune, Experimental; Fluorescent Antibody Technique; Gastrointestinal Microbiome; Gene Expression Profiling; Gene Knockdown Techniques; Glial Fibrillary Acidic Protein; Humans; Immunoblotting; Indican; Indoles; Inflammation; Interferon Type I; Interferon-beta; Limosilactobacillus reuteri; Mice; Mice, Knockout; Multiple Sclerosis; Myxovirus Resistance Proteins; Nitric Oxide Synthase Type II; Optical Imaging; Polymerase Chain Reaction; Receptor, Interferon alpha-beta; Receptors, Aryl Hydrocarbon; STAT1 Transcription Factor; Serotonin; Suppressor of Cytokine Signaling Proteins; T-Lymphocytes; Tryptophan; Tryptophanase
PubMed: 27158906
DOI: 10.1038/nm.4106 -
Theranostics 2020The dysfunctional gut-kidney axis forms a vicious circle, which eventually becomes a catalyst for the progression of chronic kidney disease (CKD) and occurrence of...
The dysfunctional gut-kidney axis forms a vicious circle, which eventually becomes a catalyst for the progression of chronic kidney disease (CKD) and occurrence of related complications. However, the pathogenic factors of CKD-associated intestinal dysfunction and its mechanism remain elusive. We first identified the protein-bound uremic toxin indoxyl sulfate (IS) as a possible contributor to intestinal barrier injury. Transepithelial electrical resistance, permeability assay and transmission electron microscopy were carried out to evaluate the damaging effect of IS on intestinal barrier in intestinal epithelial cells, IS-injected mice and CKD mice. In vitro and in vivo experiments were performed to investigate the role of IS in intestinal barrier injury and the underlying mechanism. Finally, CKD mice treated with AST-120 (an oral adsorbent for IS) and gene knockout mice were used to verify the mechanism and to explore possible interventions for IS-induced intestinal barrier injury. Transepithelial electrical resistance and the expressions of tight junction-related genes were significantly suppressed by IS in intestinal epithelial cells. In vitro experiments demonstrated that IS inhibited the expression of dynamin-related protein 1 (DRP1) and mitophagic flux, whereas DRP1 overexpression attenuated IS-induced mitophagic inhibition and intestinal epithelial cell damage. Furthermore, IS suppressed DRP1 by upregulating the expression of interferon regulatory factor 1 (IRF1), and IRF1 could directly bind to the promoter region of DRP1. Additionally, the decreased expression of DRP1 and autophagosome-encapsulated mitochondria were observed in the intestinal tissues of CKD patients. Administration of AST-120 or genetic knockout of IRF1 attenuated IS-induced DRP1 reduction, mitophagic impairment and intestinal barrier injury in mice. These findings suggest that reducing IS accumulation or targeting the IRF1-DRP1 axis may be a promising therapeutic strategy for alleviating CKD-associated intestinal dysfunction.
Topics: Adsorption; Animals; Carbon; Disease Models, Animal; Dynamins; Epithelial Cells; Gastrointestinal Agents; Humans; Indican; Interferon Regulatory Factor-1; Intestinal Diseases; Intestinal Mucosa; Kidney; Male; Mice; Mitophagy; Oxides; Permeability; Renal Elimination; Renal Insufficiency, Chronic; Tight Junctions
PubMed: 32641998
DOI: 10.7150/thno.45455 -
Journal of Molecular Medicine (Berlin,... Mar 2023Gut microbiota in interaction with intestinal host tissues influences many brain functions and microbial dysbiosis has been linked with brain disorders, such as... (Review)
Review
Gut microbiota in interaction with intestinal host tissues influences many brain functions and microbial dysbiosis has been linked with brain disorders, such as neuropsychiatric conditions and Alzheimer's disease (AD). L-tryptophan metabolites and short-chained fatty acids (SCFA) are major messengers in the microbiota-brain axis. Aryl hydrocarbon receptors (AhR) are main targets of tryptophan metabolites in brain microvessels which possess an enriched expression of AhR protein. The Ah receptor is an evolutionarily conserved, ligand-activated transcription factor which is not only a sensor of xenobiotic toxins but also a pleiotropic regulator of both developmental processes and age-related tissue degeneration. Major microbiota-produced tryptophan metabolites involve indole derivatives, e.g., indole 3-pyruvic acid, indole 3-acetaldehyde, and indoxyl sulfate, whereas indoleamine and tryptophan 2,3-dioxygenases (IDO/TDO) of intestine host cells activate the kynurenine (KYN) pathway generating KYN metabolites, many of which are activators of AhR signaling. Chronic kidney disease (CKD) increases the serum level of indoxyl sulfate which promotes AD pathogenesis, e.g., it disrupts integrity of blood-brain barrier (BBB) and impairs cognitive functions. Activation of AhR signaling disturbs vascular homeostasis in brain; (i) it controls blood flow via the renin-angiotensin system, (ii) it inactivates endothelial nitric oxide synthase (eNOS), thus impairing NO production and vasodilatation, and (iii) it induces oxidative stress, stimulates inflammation, promotes cellular senescence, and enhances calcification of vascular walls. All these alterations are evident in cerebral amyloid angiopathy (CAA) in AD pathology. Moreover, AhR signaling can disturb circadian regulation and probably affect glymphatic flow. It seems plausible that dysbiosis of gut microbiota impairs the integrity of BBB via the activation of AhR signaling and thus aggravates AD pathology. KEY MESSAGES: Dysbiosis of gut microbiota is associated with dementia and Alzheimer's disease. Tryptophan metabolites are major messengers from the gut host-microbiota to brain. Tryptophan metabolites activate aryl hydrocarbon receptor (AhR) signaling in brain. The expression of AhR protein is enriched in brain microvessels and blood-brain barrier. Tryptophan metabolites disturb brain vascular integrity via AhR signaling. Dysbiosis of gut microbiota promotes inflammation and AD pathology via AhR signaling.
Topics: Humans; Gastrointestinal Microbiome; Receptors, Aryl Hydrocarbon; Indican; Tryptophan; Alzheimer Disease; Dysbiosis; Indoles; Microbiota; Inflammation
PubMed: 36757399
DOI: 10.1007/s00109-023-02289-5 -
Toxins Apr 2020Chronic kidney disease (CKD) is associated with a high prevalence of cardiovascular diseases. During CKD, the uremic toxin indoxyl sulfate (IS)-derived from tryptophan... (Review)
Review
Chronic kidney disease (CKD) is associated with a high prevalence of cardiovascular diseases. During CKD, the uremic toxin indoxyl sulfate (IS)-derived from tryptophan metabolism-accumulates. IS is involved in the pathophysiology of cardiovascular complications. IS can be described as an endotheliotoxin: IS induces endothelial dysfunction implicated in cardiovascular morbidity and mortality during CKD. In this review, we describe clinical and experimental evidence for IS endothelial toxicity and focus on the various molecular pathways implicated. In patients with CKD, plasma concentrations of IS correlate with cardiovascular events and mortality, with vascular calcification and atherosclerotic markers. Moreover, IS induces a prothrombotic state and impaired neovascularization. IS reduction by AST-120 reverse these abnormalities. In vitro, IS induces endothelial aryl hydrocarbon receptor (AhR) activation and proinflammatory transcription factors as NF-κB or AP-1. IS has a prooxidant effect with reduction of nitric oxide (NO) bioavailability. Finally, IS alters endothelial cell and endothelial progenitor cell migration, regeneration and control vascular smooth muscle cells proliferation. Reducing IS endothelial toxicity appears to be necessary to improve cardiovascular health in CKD patients.
Topics: Animals; Cardiovascular Diseases; Endothelium, Vascular; Humans; Indican; Prognosis; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Signal Transduction; Toxins, Biological; Uremia
PubMed: 32260489
DOI: 10.3390/toxins12040229 -
Journal of Food and Drug Analysis Apr 2018Indican (indoxyl-β-D-glucoside) is present in several Chinese herbs e.g. Isatis indigotica, Polygonum tinctorium and Polygonum perfoliatum. The major metabolite of...
Indican (indoxyl-β-D-glucoside) is present in several Chinese herbs e.g. Isatis indigotica, Polygonum tinctorium and Polygonum perfoliatum. The major metabolite of indican was indoxyl sulfate (IS), an uremic toxin which was a known substrate/inhibitor of organic anion transporter (OAT) 1, OAT 3 and multidrug resistance-associated protein (MRP) 4. Methotrexate (MTX), an important immunosuppressant with narrow therapeutic window, is a substrate of OAT 1, 2, 3, 4 and MRP 1, 2, 3, 4. We hypothesized that IS, the major metabolite of oral indican, might inhibit the renal excretion of MTX mediated by OAT 1, OAT 3 and MRP 4. Therefore, this study investigated the effect of oral indican on the pharmacokinetics of MTX. Rats were orally given MTX with and without indican (20.0 and 40.0 mg/kg) in a parallel design. The serum MTX concentration was determined by a fluorescence polarization immunoassay. For mechanism clarification, phenolsulfonphthalein (PSP, 5.0 mg/kg), a probe substrate of OAT 1, OAT 3, MRP 2 and MRP 4, was intravenously given to rats with and without a intravenous bolus of IS (10.0 mg/kg) to measure the effect of IS on the elimination of PSP. The results indicated that 20.0 and 40.0 mg/kg of oral indican significantly increased the area under concentration-time curve (AUC) of MTX by 231% and 259%, prolonged the mean residence time (MRT) by 223% and 204%, respectively. Furthermore, intravenous IS significantly increased the AUC of PSP by 204% and decreased the Cl by 68%. In conclusion, oral indican increased the systemic exposure and MRT of MTX through inhibition on multiple anion transporters including OAT 1, OAT 3 and MRP 4 by the major metabolite IS.
Topics: Administration, Oral; Animals; Drug Interactions; Indican; Male; Methotrexate; Multidrug Resistance-Associated Proteins; Organic Anion Transporters; Rats; Rats, Sprague-Dawley
PubMed: 29703382
DOI: 10.1016/j.jfda.2017.11.006 -
Circulation Jan 2019
Topics: Humans; Indican; Macrophage Activation; Macrophages; Signal Transduction; Toxins, Biological; Uremia
PubMed: 30592654
DOI: 10.1161/CIRCULATIONAHA.118.037308 -
Toxins Jun 2020Vascular dysfunction is an essential element found in many cardiovascular pathologies and in pathologies that have a cardiovascular impact such as chronic kidney disease... (Review)
Review
Vascular dysfunction is an essential element found in many cardiovascular pathologies and in pathologies that have a cardiovascular impact such as chronic kidney disease (CKD). Alteration of vasomotricity is due to an imbalance between the production of relaxing and contracting factors. In addition to becoming a determining factor in pathophysiological alterations, vascular dysfunction constitutes the first step in the development of atherosclerosis plaques or vascular calcifications. In patients with CKD, alteration of vasomotricity tends to emerge as being a new, less conventional, risk factor. CKD is characterized by the accumulation of uremic toxins (UTs) such as phosphate, para-cresyl sulfate, indoxyl sulfate, and FGF23 and, consequently, the deleterious role of UTs on vascular dysfunction has been explored. This accumulation of UTs is associated with systemic alterations including inflammation, oxidative stress, and the decrease of nitric oxide production. The present review proposes to summarize our current knowledge of the mechanisms by which UTs induce vascular dysfunction.
Topics: Animals; Blood Vessels; Cresols; Fibroblast Growth Factor-23; Humans; Indican; Inflammation Mediators; Oxidative Stress; Renal Insufficiency, Chronic; Sulfuric Acid Esters; Uremia; Vascular Diseases
PubMed: 32570781
DOI: 10.3390/toxins12060404 -
International Journal of Molecular... Aug 2023Protein-bound uremic toxins (PBUTs) are associated with the progression of chronic kidney disease (CKD) and its associated morbidity and mortality. The conventional... (Review)
Review
Protein-bound uremic toxins (PBUTs) are associated with the progression of chronic kidney disease (CKD) and its associated morbidity and mortality. The conventional dialysis techniques are unable to efficiently remove PBUTs due to their plasma protein binding. Therefore, novel approaches are being developed, but these require validation in animals before clinical trials can begin. We conducted a systematic review to document PBUT concentrations in various models and species. The search strategy returned 1163 results for which abstracts were screened, resulting in 65 full-text papers for data extraction (rats ( = 41), mice ( = 17), dogs ( = 3), cats ( = 4), goats ( = 1), and pigs ( = 1)). We performed descriptive and comparative analyses on indoxyl sulfate (IS) concentrations in rats and mice. The data on large animals and on other PBUTs were too heterogeneous for pooled analysis. Most rodent studies reported mean uremic concentrations of plasma IS close to or within the range of those during kidney failure in humans, with the highest in tubular injury models in rats. Compared to nephron loss models in rats, a greater rise in plasma IS compared to creatinine was found in tubular injury models, suggesting tubular secretion was more affected than glomerular filtration. In summary, tubular injury rat models may be most relevant for the in vivo validation of novel PBUT-lowering strategies for kidney failure in humans.
Topics: Humans; Rats; Mice; Animals; Dogs; Swine; Uremic Toxins; Toxins, Biological; Models, Animal; Creatinine; Goats; Indican; Renal Insufficiency
PubMed: 37686004
DOI: 10.3390/ijms241713197