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1.
Biomed Res ; 45(2): 57-66, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38556263

RESUMO

Although patients with chronic kidney disease (CKD) have a higher risk of colorectal cancer (CRC) aggravation, the connection between these two diseases is not well understood. Recent studies have shown that both CKD and CRC aggravation are closely related to an increased abundance of indole-producing Fusobacterium nucleatum in the gut. The indole absorbed from the gut is eventually metabolized to indoxyl sulfate in the liver. Since indoxyl sulfate is involved not only in accelerating CKD progression but also in the initiation and development of its associated complications, the present study aimed to clarify whether indoxyl sulfate induces the proliferation of CRC cells. This study found that indoxyl sulfate induced the proliferation of CRC-derived HCT-116 cells by activating the aryl hydrocarbon receptor (AhR) and the proto-oncogene Akt. The AhR antagonist CH223191 and Akt inhibitor MK2206 suppressed indoxyl sulfate-induced proliferation of HCT-116 cells. We also found that indoxyl sulfate upregulated epidermal growth factor receptor (EGFR) expression, which is associated with poor prognosis of CRC, whereas CH223191 and MK2206 repressed EGFR expression. Furthermore, indoxyl sulfate increased the sensitivity of CRC cells to EGF by upregulating EGFR expression. These findings suggest that indoxyl sulfate may be an important link between CKD and CRC aggravation.


Assuntos
Compostos Azo , Neoplasias Colorretais , Pirazóis , Insuficiência Renal Crônica , Humanos , Indicã/farmacologia , Indicã/metabolismo , Proteínas Proto-Oncogênicas c-akt , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores ErbB/genética , Indóis , Proliferação de Células
2.
Cell Mol Biol Lett ; 29(1): 38, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38491448

RESUMO

Aryl hydrocarbon receptor (AhR) was originally identified as an environmental sensor that responds to pollutants. Subsequent research has revealed that AhR recognizes multiple exogenous and endogenous molecules, including uremic toxins retained in the body due to the decline in renal function. Therefore, AhR is also considered to be a uremic toxin receptor. As a ligand-activated transcriptional factor, the activation of AhR is involved in cell differentiation and senescence, lipid metabolism and fibrogenesis. The accumulation of uremic toxins in the body is hazardous to all tissues and organs. The identification of the endogenous uremic toxin receptor opens the door to investigating the precise role and molecular mechanism of tissue and organ damage induced by uremic toxins. This review focuses on summarizing recent findings on the role of AhR activation induced by uremic toxins in chronic kidney disease, diabetic nephropathy and acute kidney injury. Furthermore, potential clinical approaches to mitigate the effects of uremic toxins are explored herein, such as enhancing uremic toxin clearance through dialysis, reducing uremic toxin production through dietary interventions or microbial manipulation, and manipulating metabolic pathways induced by uremic toxins through controlling AhR signaling. This information may also shed light on the mechanism of uremic toxin-induced injury to other organs, and provide insights into clinical approaches to manipulate the accumulated uremic toxins.


Assuntos
Nefropatias , Toxinas Biológicas , Humanos , Toxinas Urêmicas , Indicã/toxicidade , Indicã/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Toxinas Biológicas/toxicidade
3.
J Cell Mol Med ; 28(7): e18192, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38506079

RESUMO

In the last decade, extensive attention has been paid to the uremic toxin indoxyl sulphate (IS) as an inducer of cardiac fibroblast (cFib) activation and cardiac fibrosis in chronic kidney disease. At cellular level, IS engages aryl hydrocarbon receptor (AhR) and regulates many biological functions. We analysed how AhR inhibition by CH-223191 (CH) and overexpression of non-functional (dominant negative, DN) nuclear factor-erythroid-2-related factor 2 (NRF2), a transcription factor recruited by AhR, modulate the response of neonatal mouse (nm) cFib to IS. We also evaluated nm-cardiomyocytes after incubation with the conditioned medium (CM) of IS±CH-treated nm-cFib. IS induced activation, collagen synthesis, TLR4 and-downstream-MCP-1, and the genes encoding angiotensinogen, angiotensin-converting enzyme, angiotensin type 1 receptor (AT1r) and neprilysin (Nepr) in nm-cFib. CH antagonized IS-initiated nm-cFib activation, but did not affect or even magnified the other features. IS promoted NRF2 nuclear translocation and expression the NRF2 target Nqo1. Both pre-incubation with CH and transfection of DN-NRF2 resulted in loss of NRF2 nuclear localization. Moreover, DN-NRF2 overexpression led to greater TLR4 and MCP-1 levels following exposure to IS. The CM of IS-primed nm-cFib and to a larger extent the CM of IS+CH-treated nm-cFib upregulated AT1r, Nepr and TNFα and myostatin genes in nm-cardiomyocytes. Hence, IS triggers pro-inflammatory activation of nm-cFib partly via AhR, and AhR-NRF2 counteract it. Strategies other than AhR inhibition are needed to target IS detrimental actions on cardiac cells.


Assuntos
Indicã , Transdução de Sinais , Camundongos , Animais , Indicã/farmacologia , Indicã/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Receptor 4 Toll-Like/genética , Fibroblastos/metabolismo
4.
Cells ; 13(6)2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38534325

RESUMO

Calcific Aortic Valve Disease (CAVD) is a significant concern for cardiovascular health and is closely associated with chronic kidney disease (CKD). Aortic valve endothelial cells (VECs) play a significant role in the onset and progression of CAVD. Previous research has suggested that uremic toxins, particularly indoxyl sulfate (IS), induce vascular calcification and endothelial dysfunction, but the effect of IS on valve endothelial cells (VECs) and its contribution to CAVD is unclear. Our results show that IS reduced human VEC viability and increased pro-calcific markers RUNX2 and alkaline phosphatase (ALP) expression. Additionally, IS-exposed VECs cultured in pro-osteogenic media showed increased calcification. Mechanistically, IS induced endothelial-to-mesenchymal transition (EndMT), evidenced by the loss of endothelial markers and increased expression of mesenchymal markers. IS triggered VEC inflammation, as revealed by NF-kB activation, and decreased integrin-linked kinase (ILK) expression. ILK overexpression reversed the loss of endothelial phenotype and RUNX2, emphasizing its relevance in the pathogenesis of CAVD in CKD. Conversely, a lower dose of IS intensified some of the effects in EndMT caused by silencing ILK. These findings imply that IS affects valve endothelium directly, contributing to CAVD by inducing EndMT and calcification, with ILK acting as a crucial modulator.


Assuntos
Estenose da Valva Aórtica , Valva Aórtica/patologia , Calcinose , Proteínas Serina-Treonina Quinases , Insuficiência Renal Crônica , Calcificação Vascular , Humanos , Indicã , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Células Endoteliais/metabolismo , Células Cultivadas , Calcificação Vascular/metabolismo , Insuficiência Renal Crônica/patologia
5.
Aging (Albany NY) ; 16(5): 4236-4249, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38385990

RESUMO

BACKGROUND AND HYPOTHESIS: Pruritus is a common and distressing symptom that affects patients with chronic kidney disease. The concentration of protein bounded uremic toxin was associated with the uremic pruritus. The aim is to assess the efficacy of AST-120 for uremic pruritus in hemodialysis patients. MATERIALS AND METHODS: The participants were enrolled and then divided into the AST-120 treatment group and control group with a ratio of 2:1. All participants underwent pre-observation screenings two weeks before the study with three visits. In the treatment phase (week 1 to week 4), the treatment group added 6g/day of AST-120 along with routine anti-pruritic treatment. Visual analog scale (VAS) and biochemical parameters were measured. RESULTS: The VAS score began to be lower in the AST-120 treatment group after the 5th visiting (p < 0.05). The reduction in indoxyl sulfate (IS) at 5th week along with TNF-alpha. The reduction ratio of indoxyl sulfate correlated with reduction of parathyroid hormone. CONCLUSION: This study has demonstrated that the four-week treatment of AST-120 decreased the severity of uremic pruritus in patients with ESRD. The concentration of IS and TNF-alpha decreased in the AST-120 treatment group. The reduction of iPTH correlated with the reduction of IS in the AST-120 treatment.


Assuntos
Carbono , Indicã , Óxidos , Uremia , Humanos , Uremia/complicações , Uremia/metabolismo , Citocinas , Fator de Necrose Tumoral alfa , Diálise Renal/efeitos adversos , Prurido/tratamento farmacológico , Prurido/etiologia
6.
Nat Commun ; 15(1): 1489, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38413572

RESUMO

Blue denim, a billion-dollar industry, is currently dyed with indigo in an unsustainable process requiring harsh reducing and alkaline chemicals. Forming indigo directly in the yarn through indican (indoxyl-ß-glucoside) is a promising alternative route with mild conditions. Indican eliminates the requirement for reducing agent while still ending as indigo, the only known molecule yielding the unique hue of blue denim. However, a bulk source of indican is missing. Here, we employ enzyme and process engineering guided by techno-economic analyses to develop an economically viable drop-in indican synthesis technology. Rational engineering of PtUGT1, a glycosyltransferase from the indigo plant, alleviated the severe substrate inactivation observed with the wildtype enzyme at the titers needed for bulk production. We further describe a mild, light-driven dyeing process. Finally, we conduct techno-economic, social sustainability, and comparative life-cycle assessments. These indicate that the presented technologies have the potential to significantly reduce environmental impacts from blue denim dyeing with only a modest cost increase.


Assuntos
Indicã , Índigo Carmim , Corantes , Plantas , Meio Ambiente
7.
Blood Purif ; 53(4): 231-242, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38262384

RESUMO

INTRODUCTION: When the kidneys or liver fail, toxic metabolites accumulate in the patient's blood, causing cardiovascular and neurotoxic complications and increased mortality. Conventional membrane-based extracorporeal blood purification procedures cannot remove these toxins efficiently. The aim of this in vitro study was to determine whether commercial hemoperfusion adsorbers are suitable for removing protein-bound retention solutes from human plasma and whole blood as well as to compare the removal to conventional hemodialysis. METHODS: For in vitro testing of the removal of protein-bound substances, whole blood and plasma were spiked with uremic retention solutes (homocysteine, hippuric acid, indoxyl sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid) and the toxins of liver failure (bilirubin, cholic acid, tryptophan, phenol). Subsequently, the protein binding of each retention solute was determined. The adsorption characteristics of the hemoperfusion adsorbers, Jafron HA and Biosky MG, both approved for the adsorption of protein-bound uremic retention solutes and Cytosorb, an adsorber recommended for adsorption of cytokines, were tested by incubating them in spiked whole blood or plasma for 1 h. Subsequently, the adsorption characteristics of the adsorbers were tested in a dynamic system. For this purpose, a 6-h in vitro hemoperfusion treatment was compared with an equally long in vitro hemodialysis treatment. RESULTS: Hippuric acid, homocysteine, indoxyl sulfate, and tryptophan were most effectively removed by hemodialysis. Bilirubin and cholic acid were removed best by hemoperfusion with Cytosorb. A treatment with Jafron HA and Biosky MG showed similar results for the adsorption of the tested retention solutes and were best for removing phenol. 3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid could not be removed with any treatment method. DISCUSSION/CONCLUSION: A combination of hemodialysis with hemoperfusion seems promising to improve the removal of some toxic metabolites in extracorporeal therapies. However, some very strongly protein-bound metabolites cannot be removed adequately with the adsorbers tested.


Assuntos
Hipuratos , Toxinas Biológicas , Uremia , Humanos , Toxinas Urêmicas , Indicã , Triptofano/metabolismo , Diálise Renal/efeitos adversos , Ligação Proteica , Fenóis , Bilirrubina , Ácido Cólico , Homocisteína/metabolismo
8.
J Alzheimers Dis ; 97(3): 1393-1405, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38250771

RESUMO

BACKGROUND: Cognitive impairment (CI) is one of the major complications in chronic kidney disease patients, especially those with end-stage renal disease (ESRD). Limited biomarkers have been found that can significantly predict ESRD-associated cognitive decline. OBJECTIVE: This cohort study aimed to investigate de novo biomarkers for diagnosis of the ESRD-associated CI. METHODS: In this cohort study, qualified samples were divided into control (with an estimated glomerular filtration rate (eGFR) of≥60 mL/min and a Mini-Mental State Examination (MMSE) score of > 27), ESRD without CI (eGFR < 15 and MMSE > 27), and ESRD with CI (eGFR < 15 and MMSE < 27) groups. Levels of plasma amyloid-ß (Aß)1 - 42, serum indoxyl sulfate, and hematologic and biochemical parameters were measured. RESULTS: Compared to the control group, levels of blood urea nitrogen, creatinine, and indoxyl sulfate were elevated in ESRD patients both without and with CI. Interestingly, ESRD patients with CI had the lowest levels of serum albumin. In contrast, levels of plasma Aß1 - 42 were significantly higher in the ESRD with CI group than in the control and ESRD without CI groups. In addition, the ratio of plasma Aß1 - 42 over serum albumin was significantly higher in the ESRD with CI group than in the control or ESRD without CI groups. Importantly, the area under the receiver operating characteristic curve (AUROC) for CI in the total population by the ratio of Aß1 - 42 over albumin was 0.785 and significant (p < 0.05). CONCLUSIONS: This cohort study has shown that the ratio of plasma Aß1 - 42 over serum albumin can be a de novo biomarker for the diagnosis and prognosis of ESRD-associated cognitive decline.


Assuntos
Disfunção Cognitiva , Falência Renal Crônica , Humanos , Estudos de Coortes , Albumina Sérica , Indicã , Falência Renal Crônica/complicações , Taxa de Filtração Glomerular , Biomarcadores , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/complicações , Peptídeos beta-Amiloides
9.
ACS Appl Mater Interfaces ; 16(5): 6589-6604, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38282580

RESUMO

Chronic kidney disease (CKD), a pressing global health issue, affects millions and leads to end-stage renal disease (ESRD). Hemodialysis (HD) is a crucial treatment for ESRD, yet its limited efficiency in removing protein-bound uremic toxins (PBUTs) results in high morbidity and mortality rates. A high affinity of pharmaceutical drugs for human serum albumin (HSA) can be leveraged to compete effectively with PBUTs for the same HSA binding sites, thereby enabling them to be capable of displacing these toxins. One such drug is ibuprofen (IBF), known for its very high affinity for HSA and sharing the same binding site as indoxyl sulfate (IS). This study explores the development of IBF-immobilized cellulose acetate-based (CA-based) thin films. The films were created by reacting CA with IBF-modified silica precursors at varying concentrations. The presence of IBF in CA/TEOS/APTES-IBF-3 and CA/TEOS-IBF-25 films, containing 3 and 25 wt % IBF, respectively, was confirmed through 1H NMR spectra. Competitive displacement binding assays indicated that while the incorporation of 3 wt % IBF showed no significant enhancement in IS displacement, the 25 wt % IBF film increased the dialyzed IS by 1.3 when normalized to non-IBF films. Furthermore, there was a 1.2-fold decrease in the total percentage of IS, and the free percentage of IS increased 1.3 to 3.0 times. Although direct systemic infusion of IBF in HD patients achieves a 2.4 times higher removal of IS, it is impractical due to the risks it poses to ESRD patients. The IBF-immobilized films offer the advantage of localized binding, thus eliminating the need for systemic exposure. This innovative approach lays a foundation for developing more efficient HD membranes, aiming to address the challenging issue of PBUT elimination and potentially enhance the quality of life and treatment outcomes for ESRD patients.


Assuntos
Falência Renal Crônica , Toxinas Biológicas , Uremia , Humanos , Toxinas Urêmicas , Ibuprofeno , Qualidade de Vida , Ligação Proteica , Falência Renal Crônica/terapia , Diálise Renal , Albumina Sérica Humana/metabolismo , Indicã
10.
Sci Rep ; 14(1): 2583, 2024 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-38297036

RESUMO

Indoxyl sulfate (IS), an agonist of aryl hydrocarbon receptors (AhR), can accumulate in patients with chronic kidney disease, but its direct effect on bone is not clear. The present study investigated the effect of chronic exposure to low (100 mg/kg b.w.; 100 IS) and high (200 mg/kg b.w.; 200 IS) dose of IS on bone AhR pathway, sirtuins (SIRTs) expression, oxidative DNA damage and bone mineral status in Wistar rats. The accumulation of IS was observed only in trabecular bone tissue in both doses. The differences were observed in the bone parameters, depending on the applied IS dose. The exposure to 100 IS increased AhR repressor (AhRR)-CYP1A2 gene expression, which was associated with SIRT-1, SIRT-3 and SIRT-7 expression. At the low dose group, the oxidative DNA damage marker was unchanged in the bone samples, and it was inversely related to the abovementioned SIRTs expression. In contrast, the exposure to 200 IS reduced the expression of AhRR, CYP1A, SIRT-3 and SIRT-7 genes compared to 100 IS. The level of oxidative DNA damage was higher in trabecular bone in 200 IS group. Femoral bone mineral density was decreased, and inverse relations were noticed between the level of trabecular oxidative DNA damage and parameters of bone mineral status. In conclusion, IS modulates AhR-depending signaling affecting SIRTs expression, oxidative DNA damage and bone mineral status in a dose dependent manner.


Assuntos
Indicã , Sirtuínas , Humanos , Ratos , Animais , Ratos Wistar , Receptores de Hidrocarboneto Arílico/metabolismo , Estresse Oxidativo , Expressão Gênica , Sirtuínas/genética , Sirtuínas/metabolismo
11.
mBio ; 15(2): e0269223, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38226819

RESUMO

A recent study published in mBio by Nemet et al. revealed the critical role played by two gut microbiota members in producing the metabolites indoxyl sulfate (IS) and p-cresol sulfate (pCS) (I. Nemet, M. Funabashi,X. S. Li, M. Dwidar, et al., 2023, mBio 14:e01331-23, https://doi.org/10.1128/mbio.01331-23). Understanding microbial pathways leading to IS and pCS production is crucial because they are connected to a pre-thrombotic profile, and having high levels of these metabolites increases the risk of cardiovascular diseases (CVD). Hence, this study can offer vital insights into assessing the risk for CVD and identifying potential treatment targets for this disease.


Assuntos
Doenças Cardiovasculares , Cresóis , Microbiota , Ésteres do Ácido Sulfúrico , Trombose , Humanos , Indicã
12.
ESC Heart Fail ; 11(1): 466-474, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38041505

RESUMO

AIMS: This retrospective cohort study aimed to be the first to evaluate the association between plasma protein-bound uremic toxins (PBUTs) concentrations, echocardiographic parameters of heart failure (HF), and incident HF events in patients with chronic kidney disease (CKD) not on dialysis. METHODS AND RESULTS: Retrospective, single-centre, cohort study at the Ghent University Hospital, Belgium. Adults with CKD stages G1-G5, not on dialysis, could be included. Exclusion criteria were ongoing pregnancy, age <18 years, active acute infection, active malignancy, history of transplantation, or a cardiovascular event within 3 months prior to inclusion. Free and total concentrations of five PBUTs were quantified at baseline: indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glucuronide (pCG), indole-3 acetic acid (IAA), and hippuric acid (HA). Patients were grouped into three echocardiographic categories: normal left ventricular ejection fraction (LVEF) and normal left ventricular end-diastolic pressure (LVEDP), normal LVEF and increased LVEDP, and reduced LVEF, based on available echocardiographic data in a time interval of ±6 months around the plasma sample collection. A total of 523 patients were included between January 2011 and January 2014. Echocardiographic data within the predefined timeframe were available for 210 patients (40% of patients). Levels of pCG and pCS were significantly higher in patients with reduced (<50%) versus normal LVEF (P < 0.05). After a median follow-up 5.5 years, 43 (8.4%) patients reached the composite endpoint of hospitalization or mortality due to HF. Free fractions of IxS, pCS, and pCG showed the strongest association with clinical outcome: free IxS: HR 1.71 (95% CI 1.11-2.63; P = 0.015), free pCS: HR 1.82 (95% CI 1.11-3.01; P = 0.019), and free pCG: HR 1.67 (95% CI 1.08-2.58; P = 0.020), and these results were independent of age, gender, body mass index, diabetes, and systolic blood pressure. In models that were also adjusted for serum creatinine, the free fractions of these PBUTs remained significant. CONCLUSIONS: Elevated free concentrations of IxS, pCG, and pCS were independently associated with an increased risk of HF events in non-dialysed CKD patients. Further research is necessary to confirm these findings and investigate the potential impact of PBUT-lowering interventions on HF events in this patient group.


Assuntos
Insuficiência Cardíaca , Insuficiência Renal Crônica , Toxinas Biológicas , Uremia , Adulto , Humanos , Adolescente , Toxinas Urêmicas , Estudos Retrospectivos , Uremia/etiologia , Volume Sistólico , Estudos de Coortes , Função Ventricular Esquerda , Insuficiência Cardíaca/complicações , Indicã
13.
J Ren Nutr ; 34(1): 26-34, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37468049

RESUMO

OBJECTIVE: To determine serum and urine concentrations of the uremic retention solutes (URSs), indoxyl sulfate (IS), p-cresol sulfate (PCS), and trimethylamine N-oxide (TMAO), and gut microbiota composition in individuals with moderate chronic kidney disease (CKD) compared with matched adults without CKD in a 6-day controlled feeding study. DESIGN AND METHODS: This study was a secondary analysis in which 8 adults with moderate CKD were matched for age, sex, and race with 8 adults without CKD in a parallel-arm, 6-day controlled feeding study. IS, PCS, and TMAO were quantified using liquid chromatography-mass spectrometry in fecal samples, fasting serum, and fasting spot urine samples collected at the end of the feeding period. RESULTS: Fasting serum URS concentrations were 2.8 to 4.9x higher in CKD compared to controls (all P < .05). No differences were found in the composition of the gut microbiota between patients with and without CKD when analyzing samples for α-diversity, ß-diversity, and only minor abundance differences across taxa were apparent. Estimated glomerular filtration rate (eGFR) was inversely related to each serum URS in the whole cohort (all P < .01). However, within groups the relationships between eGFR and serum URS remained strong for CKD patients for IS and TMAO (both P < .05) but weakened for PCS (P = .10). eGFR was only correlated with urine PCS in the whole cohort (P = .03); within groups, no correlation for eGFR with any urine URS was observed. Only urine TMAO was higher in CKD compared to controls (P < .05). CONCLUSION: Serum URS concentrations are elevated in adults with CKD compared to matched non-CKD adults without differences in gut microbiota composition after consuming the same controlled study diet for 6 days. Future studies are needed to determine if specific dietary components may differentially alter the microbiota and URS.


Assuntos
Microbioma Gastrointestinal , Insuficiência Renal Crônica , Adulto , Humanos , Toxinas Urêmicas , Metilaminas , Indicã
14.
Neurosci Lett ; 820: 137594, 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38096971

RESUMO

Patients with end-stage renal disease often have neurological disorders, with a higher incidence of memory impairment or epilepsy than in the general population. Patients undergoing hemodialysis are particularly exposed to the biological effects of uremic toxins. Indoxyl sulfate (IS) is one of the most potent uremic toxins; however, its possible effects on seizure susceptibility or memory functions have yet to be elucidated. In the current study, we focused on investigating the possible convulsant and amnesic effects of IS in recognized animal models. The study was performed on adult male Swiss mice. IS and scopolamine (SCO) were administered intraperitoneally (i.p.), and pentylenetetrazole (PTZ) was injected subcutaneously (s.c.). All substances were given as single injections. Acute IS administration (400 mg/kg) led to its accumulation in the brain. IS at doses of 200 and 400 mg/kg decreased the PTZ convulsive threshold, and at the same doses, it did not significantly affect the threshold for electroconvulsions. IS (200 and 400 mg/kg) did not impair learning in the passive avoidance test and did not increase the SCO-induced memory impairment in this test. IS increased lipid peroxidation, decreased the level of reduced glutathione, and reduced the activity of superoxide dismutase and catalase in mouse brains. Exposure to IS did not significantly change the activity of acetylcholinesterase in the brain tissue. This study shows that acute exposure to IS induces oxidative stress in the brain and potentiates PTZ-induced seizures in mice. Further studies are needed to find out whether IS-induced oxidative stress may affect epileptic seizures and/or epileptogenesis.


Assuntos
Epilepsia , Indicã , Humanos , Adulto , Camundongos , Masculino , Animais , Indicã/toxicidade , Toxinas Urêmicas , Acetilcolinesterase , Encéfalo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Epilepsia/tratamento farmacológico , Estresse Oxidativo , Pentilenotetrazol/toxicidade , Anticonvulsivantes/farmacologia , Modelos Animais de Doenças
15.
J Cutan Med Surg ; 28(1): 44-50, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38156627

RESUMO

BACKGROUND: Pruritus is a common complaint in patients with end-stage renal disease. Indoxyl sulfate (IS) is a tryptophan end metabolite extremely renal excreted. Activated charcoal can interfere with IS intestinal absorption. OBJECTIVES: To evaluate the serum level of IS and the effect of activated charcoal on uremic pruritus. MATERIALS AND METHODS: In all, 135 participants were divided into 2 main groups. In total, 45 normal and healthy individuals as a control group and 90 patients on regular hemodialysis; 45 of these patients had uremic pruritus and the other 45 were not complaining of uremic pruritus. Serum IS was measured. Activated charcoal was used by patients with uremic pruritus. The severity of pruritus and Dermatology Life Quality Index (DLQI) were assessed. RESULTS: The serum IS was significantly elevated in uremic patients than in control subjects (P < .001) and significantly elevated in uremic patients without pruritus (P < .001). Furthermore, there were positive significant correlations between the serum IS and both severity of pruritus (P < .001) and DLQI (P < .001). After activated charcoal usage, there was a significant decrease in IS level with the improvement of pruritus and quality of life of patients. CONCLUSIONS: IS may play a role in uremic pruritus. Activated charcoal could be considered a treatment for uremic pruritus.


Assuntos
Carvão Vegetal , Uremia , Humanos , Carvão Vegetal/uso terapêutico , Uremia/complicações , Indicã , Qualidade de Vida , Prurido/tratamento farmacológico , Prurido/etiologia
16.
Nephrol Ther ; 19(7): 607-615, 2023 12 20.
Artigo em Francês | MEDLINE | ID: mdl-38059844

RESUMO

Patients with chronic kidney disease (CKD) have an increased risk of cognitive disorders, presenting as vascular dementia, compared with the general population. These cognitive disorders occur early during the course of the kidney disease and evolve in parallel with the decline in glomerular filtration rate. They affect 30 to 80 % of patients with stage 5 CKD. Kidney transplantation only partially improves cognitive impairment. In this narrative review, we summarize the epidemiology and recent clinical and experimental data on cognitive impairment in CKD and discuss the potential specific mechanisms. Among the factors associated with cognitive impairment, the accumulation of uremic toxins such as indoxyl sulfate appears to be a specific risk factor for cognitive decline. These toxins have an endothelial toxicity that can disrupt the cerebral endothelium. The rupture of the blood-brain barrier (BBB) is a mechanism implicated in several neurodegenerative pathologies and systemic diseases with cerebral tropism. Recent experimental findings in CKD indicate that disruption of the BBB appears to be an important mechanism behind cognitive impairment in CKD. In murine models of CKD, increased BBB permeability is linked to memory impairment and aryl hydrocarbon receptor activation following accumulation of circulating indoxyl sulfate. This disruption of the BBB could also have harmful consequences for stroke susceptibility and drug neurotoxicity in CKD patients.


Les patients atteints de maladie rénale chronique (MRC) présentent un risque accru de troubles neurocognitifs par rapport à la population générale, se présentant sous la forme d'une démence vasculaire. Ces troubles cognitifs interviennent précocement dans la maladie rénale et évoluent en parallèle au déclin du débit de filtration glomérulaire. Ils concernent 30 à 80 % des patients au stade 5 de la MRC. La transplantation rénale n'améliore que partiellement les troubles cognitifs. Dans cette revue narrative, nous résumons l'épidémiologie et les données cliniques et expérimentales récentes sur les troubles cognitifs dans la MRC, et nous en abordons les mécanismes spécifiques potentiels. Parmi les facteurs associés aux atteintes cognitives, l'accumulation des toxines urémiques, comme l'indoxyl sulfate, apparaît comme un facteur de risque spécifique de déclin cognitif. Ces toxines possèdent une toxicité endothéliale pouvant perturber l'endothélium cérébral. La rupture de la barrière hémato-encéphalique (BHE) est un mécanisme impliqué dans plusieurs pathologies neuro-dégénératives et des maladies systémiques à tropisme cérébral. Les résultats de travaux expérimentaux récents dans la MRC indiquent que la rupture de la BHE semble être un mécanisme important des troubles cognitifs au cours de la MRC. Dans les modèles murins de MRC, la perméabilité accrue de la BHE est liée à l'atteinte de la mémoire et à l'activation d'Aryl hydrocarbon Receptor suite à l'accumulation d'indoxyl sufate circulant. Cette rupture de la BHE pourrait également avoir des conséquences néfastes sur la susceptibilité aux accidents vasculaires cérébraux (AVC) et à la neurotoxicité médicamenteuse chez les patients MRC.


Assuntos
Disfunção Cognitiva , Insuficiência Renal Crônica , Toxinas Biológicas , Uremia , Humanos , Camundongos , Animais , Barreira Hematoencefálica , Toxinas Urêmicas , Indicã , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Disfunção Cognitiva/etiologia , Uremia/complicações
17.
Molecules ; 28(23)2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-38067420

RESUMO

Asperulosidic acid is a bioactive iridoid isolated from Hedyotis diffusa Willd. with anti-inflammatory and renal protective effects. However, its mechanism on renal interstitial fibrosis has not been elucidated yet. The present study aims to explore whether asperulosidic acid could retard renal fibrosis by reducing the circulating indoxyl sulfate (IS), which is a uremic toxin and accelerates chronic kidney disease progression by inducing renal fibrosis. In this paper, a unilateral ureteral obstruction (UUO) model of Balb/C mice was established. After the mice were orally administered with asperulosidic acid (14 and 28 mg/kg) for two weeks, blood, liver and kidney were collected for biochemical, histological, qPCR and Western blot analyses. Asperulosidic acid administration markedly reduced the serum IS level and significantly alleviated the histological changes in glomerular sclerosis and renal interstitial fibrosis. It is noteworthy that the mRNA and protein levels of the organic anion transporter 1 (OAT1), OAT3 and hepatocyte nuclear factor 1α (HNF1α) in the kidney were significantly increased, while the mRNA expressions of cytochrome P450 2e1 (Cyp2e1) and sulfotransferase 1a1 (Sult1a1) in the liver were not altered after asperulosidic acid administration. These results reveal that asperulosidic acid could accelerate the renal excretion of IS by up-regulating OATs via HNF1α in UUO mice, thereby alleviating renal fibrosis, but did not significantly affect its production in the liver, which might provide important information for the development of asperulosidic acid.


Assuntos
Nefropatias , Transportadores de Ânions Orgânicos , Insuficiência Renal Crônica , Obstrução Ureteral , Camundongos , Animais , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia , Indicã/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Nefropatias/metabolismo , Rim , Insuficiência Renal Crônica/metabolismo , Fibrose , RNA Mensageiro/metabolismo
18.
Cell Cycle ; 22(21-22): 2409-2423, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-38129288

RESUMO

Chronic kidney disease (CKD) patients have a high risk of cardiovascular disease. Indoxyl sulfate (IS) is a uremic toxin that has been shown to inhibit nitric oxide production and cause cell senescence by inducing oxidative stress. High-density lipoprotein (HDL) has a protective effect on the cardiovascular system; however, its impacts on IS-damaged endothelial cells are still unknown. This study aimed to explore the effects of exogenous supplement of HDL on vascular endothelial cells in a uremia-mimic environment. Tube formation, migration, adhesion, and senescence assays were used to evaluate the cell function of human aortic endothelial cells (HAECs). Reactive oxygen species generation was measured by using Amplex red assay. L-NAME and MCI186 were used as a nitric oxide synthase inhibitor and a free radical scavenger, respectively. HDL exerted anti-inflammatory and antioxidant effects via HIF-1α/HO-1 activation and IL-1ß/TNF-α/IL-6 inhibition in IS-stimulated HAECs. HDL improved angiogenesis ability through upregulating Akt/eNOS/VEGF/SDF-1 in IS-stimulated HAECs. HDL decreased endothelial adhesiveness via downregulating VCAM-1 and ICAM-1 in IS-stimulated HAECs. Furthermore, HDL reduced cellular senescence via upregulating SIRT1 and downregulating p53 in IS-stimulated HAECs. Importantly, the above beneficial effects of HDL were mainly due to its antioxidant ability. In conclusion, HDL exerted a comprehensive protective effect on vascular endothelial cells against damage from IS through its antioxidant ability. The results of this study might provide a theoretical basis for potential HDL supplementation in CKD patients with endothelial damage.


Assuntos
Antioxidantes , Insuficiência Renal Crônica , Humanos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Lipoproteínas HDL/farmacologia , Lipoproteínas HDL/metabolismo , Indicã/farmacologia , Células Endoteliais/metabolismo , Insuficiência Renal Crônica/metabolismo
19.
J Med Chem ; 66(24): 17074-17085, 2023 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-38103027

RESUMO

There are a number of reports about anticancer activity of indole derivatives. In this study, we investigated the role of indoxyl sulfate (IS) for its selective anticancer activity on colon cancer cells. IS treatment on HCT-116 and HT-29 human epithelial adenocarcinoma cells led to a decrease in cell proliferation, cell viability, and ATP content. Colon cancer cells showed a 10% increase in cell apoptosis in comparison to control. Due to IS treatment, cell morphology got distorted, cell number found decreased, intracellular vesicles formed, and cells were found floating in the media. Cells also showed a loss in membrane integrity and a decrease in colony-forming ability and ceased at the G2/M phase of the cell cycle. No significant change was noted in the level of inflammatory cytokines IL-17A, IL-1ß, and TNF-α, histology, length of intestine, and spleen after 100 mM IS treatment to balb/c mice. These observations indicate the selective anticancer effect of IS on colon cancer cells.


Assuntos
Neoplasias do Colo , Indicã , Animais , Camundongos , Humanos , Indicã/farmacologia , Apoptose , Células HT29 , Proliferação de Células , Neoplasias do Colo/patologia
20.
Medicina (Kaunas) ; 59(12)2023 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-38138292

RESUMO

Background and Objectives: The present study aims to investigate the association between gut microbiota's oxalate-degrading activity (ODA) and the risk of developing cardiovascular disease (CVD) over a three-year follow-up period in a cohort of patients undergoing kidney replacement therapy (KRT). Additionally, various factors were examined to gain insight into the potential mechanisms underlying the ODA-CVD link. Materials and Methods: A cohort of 32 KRT patients and 18 healthy volunteers was enrolled in this prospective observational pilot study. Total fecal ODA, routine clinical data, plasma oxalic acid (POx), serum indoxyl sulfate, lipid profile, oxidative stress, and proinflammatory markers were measured, and the patients were followed up for three years to assess CVD events. Results: The results revealed that patients with kidney failure exhibited significantly lower total fecal ODA levels compared to the healthy control group (p = 0.017), with a higher proportion showing negative ODA status (≤-1% per 0.01 g) (p = 0.01). Negative total fecal ODA status was associated with a significantly higher risk of CVD events during the three-year follow-up period (HR = 4.1, 95% CI 1.4-16.3, p = 0.003), even after adjusting for potential confounders. Negative total fecal ODA status was significantly associated with elevated POx and indoxyl sulfate levels and linked to dyslipidemia, increased oxidative stress, and inflammation, which are critical contributors to CVD. Conclusions: The findings contribute novel insights into the relationship between gut microbiota's ODA and cardiovascular health in patients undergoing KRT, emphasizing the need for further research to elucidate underlying mechanisms and explore potential therapeutic implications of targeting gut microbiota's ODA in this vulnerable population.


Assuntos
Doenças Cardiovasculares , Microbioma Gastrointestinal , Insuficiência Renal , Humanos , Estudos Prospectivos , Oxalatos , Indicã , Projetos Piloto , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/epidemiologia
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