The Role of the Glyoxalase Pathway in Reducing Mesothelial Toxicity of Glucose Degradation Products

Background The glucose degradation products (GDP) present in conventional peritoneal dialysis fluids (PDF) may exert adverse effects toward human peritoneal mesothelial cells (HPMC). Some GDP can be detoxified by the glyoxalase/glutathione pathway. It has been shown that the addition of glyoxalase I (GLO-I) and reduced glutathione (GSH) to PDF effectively eliminates GDP. We have therefore examined the GLO-I/GSH system in HPMC and assessed the impact of GLO-I/GSH-treated PDF on the viability and function of HPMC. Methods Heat-sterilized PDF (H-PDF) was incubated in the presence or absence of GLO-I and GSH for 1 hour at 37°C, and then mixed with an equal volume of serum-free M199 medium and applied to HPMC in culture. After 24 hours, HPMC were assessed for viability, the release of interleukin-6, GLO-I activity, and cellular glutathione. The effects were compared to those exerted by filter-sterilized PDF (F-PDF), which was devoid of GDP. Results Exposure of HPMC to H-PDF resulted in reduced GLO-I activity, GSH depletion, and a decrease in cell viability. Pretreatment of H-PDF with either a combination of GLO-I and GSH or GSH alone markedly reduced inhibitory effects of H-PDF toward HPMC, as measured by cell viability and interleukin-6 generation. Exposure of HPMC to the GSH precursor L-2-oxothiazolidine-carboxylic acid increased cellular GSH and prevented the loss of GLO-I activity in response to H-PDF. Conclusions Exposure to conventional GDP-rich PDF impairs the activity of the glyoxalase/glutathione system in HPMC. Pretreatment of PDF with GSH or replenishment of cellular GSH protects HPMC against GDP-mediated toxicity.

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Prolonged Exposure to Glucose Degradation Products Impairs Viability and Function of Human Peritoneal Mesothelial Cells

Journal of the American Society of Nephrology ◽

10.1681/asn.v12112434 ◽

2001 ◽

Vol 12 (11) ◽

pp. 2434-2441 ◽

Cited By ~ 1

Author(s):

JANUSZ WITOWSKI ◽

JUSTYNA WISNIEWSKA ◽

KATARZYNA KORYBALSKA ◽

THORSTEN O. BENDER ◽

ANDRZEJ BREBOROWICZ ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Cell Viability ◽

Degradation Products ◽

Mesothelial Cells ◽

Peritoneal Mesothelial Cells ◽

Glucose Degradation Products ◽

Human Peritoneal Mesothelial Cells ◽

And Function ◽

The Impact

Abstract. Bioincompatibility of peritoneal dialysis fluids (PDF) has been linked to the presence of glucose degradation products (GDP). Previous experiments have shown that short-term exposure to several GDP at concentrations found in commercially available PDF had no significant effect on human peritoneal mesothelial cells (HPMC). During continuous ambulatory peritoneal dialysis, however, cells are continually exposed to GDP for extended periods of time. Thus, the impact of GDP on HPMC during long-term exposure was assessed. HPMC were cultured for up to 36 d in the presence of 6 identified GDP (acetaldehyde, formaldehyde, furaldehyde, glyoxal, methylglyoxal, and 5-HMF) at doses that reflect their concentrations in conventional PDF. At regular time intervals, the ability of HPMC to secrete cytokines (interleukin-6 [IL-6]) and extracellular matrix molecules (fibronectin) was evaluated. In addition, cell viability, morphology, and proliferative potential were assessed. Exposure to GDP resulted in a significant reduction in mesothelial IL-6 and fibronectin release. Approximately 80% of this decrease occurred during the first 12 d of the exposure and was paralleled by a gradual loss of cell viability and development of morphologic alterations. After 36 d of exposure, the number of cells in GDP-treated cultures was reduced by nearly 60%. However, GDP-treated cells were able to resume normal proliferation when transferred to a normal GDP-free medium. HPMC viability and function may be impaired during long-term exposure to clinically relevant concentrations of GDP, which suggests a potential role of GDP in the pathogenesis of peritoneal membrane dysfunction during chronic peritoneal dialysis.

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Glucose Degradation Products and Peritoneal Membrane Function

Peritoneal Dialysis International ◽

10.1177/089686080102100218 ◽

2001 ◽

Vol 21 (2) ◽

pp. 201-207 ◽

Cited By ~ 15

Author(s):

Janusz Witowski ◽

Thorsten O. Bender ◽

Gerhard M. Gahl ◽

Ulrich Frei ◽

Achim Jörres

Keyword(s):

Peritoneal Dialysis ◽

Cell Viability ◽

Degradation Products ◽

Membrane Function ◽

Peritoneal Mesothelial Cells ◽

Glucose Degradation Products ◽

And Function ◽

The Impact ◽

Dialysis Fluids

Background The bioincompatibility of peritoneal dialysis fluids (PDF) in current use has been partially attributed to the presence of glucose degradation products (GDPs), which are generated during heat sterilization of PDF. Several of the GDPs have been identified and we have recently demonstrated that these GDPs per se may impair the viability and function of human peritoneal mesothelial cells (HPMC) in vitro. It is also possible that GDP-related toxicity is further exacerbated by the milieu of PDF. We review the current literature on GDP and present the results of experiments comparing the impact of heat- and filter-sterilized PDF on the viability and function of HPMC. Methods Peritoneal dialysis fluids with low (1.5%) and high (4.25%) glucose concentrations were laboratory prepared according to the standard formula and sterilized either by heat (H-PDF; 121°C, 0.2 MPa, 20 minutes) or filtration (F-PDF; 0.2 μ). The buildup of GDP was confirmed by UV absorbance at 284 nm. Confluent HPMC monolayers were exposed to these solutions mixed 1:1 with standard M199 culture medium. After 24 hours, cell viability was assessed with the MTT assay, and interleukin-1β–stimulated monocyte chemotactic protein-1 (MCP-1) release with specific immunoassay. Results Exposure of HPMC to H-PDF resulted in a significant decrease in cell viability, with solutions containing 4.25% glucose being more toxic than 1.5% glucose-based PDF (27.4% ± 3.4% and 53.4% ± 11.0% of control values, respectively). In contrast, viability of HPMC exposed to F-PDF was not different from that of control cells. Moreover, treatment with H-PDF impaired the release of MCP-1 from HPMC to a significantly greater degree compared to F-PDF (17.4% and 24.9% difference for low and high glucose PDF, respectively). Conclusions Exposure of HPMC to H-PDF significantly impairs cell viability and the capacity for generating MCP-1 compared to F-PDF. This effect is likely to be mediated by GDPs present in H-PDF but not in F-PDF.

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Glucose degradation products downregulate ZO-1 expression in human peritoneal mesothelial cells: the role of VEGF

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfh814 ◽

2005 ◽

Vol 20 (7) ◽

pp. 1336-1349 ◽

Cited By ~ 37

Author(s):

Joseph C. K. Leung ◽

Loretta Y. Y. Chan ◽

Felix F. K. Li ◽

Sydney C. W. Tang ◽

Kwok Wa Chan ◽

...

Keyword(s):

Degradation Products ◽

Mesothelial Cells ◽

Peritoneal Mesothelial Cells ◽

Glucose Degradation Products ◽

Human Peritoneal Mesothelial Cells

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Peritoneal Dialysis Solutions Low in Glucose Degradation Products—evidence for Clinical Benefits

Peritoneal Dialysis International ◽

10.1177/089686080802803s23 ◽

2008 ◽

Vol 28 (3_suppl) ◽

pp. 123-127

Author(s):

Tadashi Tomo

Keyword(s):

Peritoneal Dialysis ◽

Vascular Function ◽

Degradation Products ◽

Peritoneal Mesothelial Cells ◽

Advanced Glycosylation End Products ◽

Glucose Degradation Products ◽

Peritoneal Dialysis Fluid ◽

Clinical Benefits ◽

Human Peritoneal Mesothelial Cells ◽

Peritoneal Function

In Japan, two types of new peritoneal dialysis fluid (PDF) are ordinarily used: two-chambered PDF, and icodextrin PDF. Two-chambered PDF has several biocompatible characteristics, one being low glucose degradation products (GDPs). Of the several GDPs in PDF, 3,4-dideoxyglucosone-3-ene (3,4-DGE) is thought to be strongly associated with the cytotoxicity of standard PDF. Using a PDF low in GDPs may reduce exposure of the peritoneum to 3,4-DGE, helping to preserve peritoneal function in PD patients. Additionally, use of a PDF low in GDPs may reduce plasma levels of advanced glycosylation end-products in PD patients, a change that may help to preserve vascular function in PD patients. Peritoneal rest for 24 hours after exposure to a PDF with low GDPs improves the activity of human peritoneal mesothelial cells. As compared with the use of standard PDF, the use of low-GDP PDF in combination therapy (peritoneal dialysis plus hemodialysis) may more effectively preserve peritoneal function. The new PDF low in GDPs has bio-compatible characteristics relative to peritoneum and system that may help to preserve peritoneal function or reduce complications such as atherosclerosis or dialysis-related amyloidosis in dialysis patients.

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[PP-132] Transcriptome Analysis in Human Peritoneal Mesothelial Cells Exposed to PD Solution Low in Glucose Degradation Products

Peritoneal Dialysis International ◽

10.1177/089686080802800604 ◽

2008 ◽

Vol 28 (6) ◽

pp. 576-576

Author(s):

S. Steppan ◽

J. Witowski ◽

K. Korybalska ◽

A. Jörres ◽

J. Passlick–Deetjen

Keyword(s):

Transcriptome Analysis ◽

Degradation Products ◽

Mesothelial Cells ◽

Peritoneal Mesothelial Cells ◽

Glucose Degradation Products ◽

Human Peritoneal Mesothelial Cells

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Gab1 in livers with persistent hepatocyte apoptosis has an antiapoptotic effect and reduces chronic liver injury, fibrosis and tumorigenesis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00370.2020 ◽

2021 ◽

Author(s):

Tetsuo Takehara ◽

Naoki Mizutani ◽

Hayato Hikita ◽

Yoshinobu Saito ◽

Yuta Myojin ◽

...

Keyword(s):

Chronic Hepatitis ◽

Liver Injury ◽

Cell Viability ◽

Liver Regeneration ◽

Adaptor Protein ◽

Chronic Liver ◽

Hepatocyte Apoptosis ◽

Chronic Liver Injury ◽

The Impact

Grb2-associated binder 1 (Gab1) is an adaptor protein that is important for intracellular signal transduction by receptor tyrosine kinases that are receptors for various growth factors and plays an important role in rapid liver regeneration after partial hepatectomy and during acute hepatitis. On the other hand, mild liver regeneration is induced in livers of individuals with chronic hepatitis, where hepatocyte apoptosis is persistent; however, the impact of Gab1 on such livers remains unclear. We examined the role of Gab1 in chronic hepatitis. Gab1 knockdown enhanced the decrease in cell viability and apoptosis induced by ABT-737, a Bcl-2/-xL/-w inhibitor, in BNL.CL2 cells, while cell viability and caspase activity were unchanged in the absence of ABT-737. ABT-737 treatment induced Gab1 cleavage to form p35-Gab1. p35-Gab1 was also detected in the livers of mice with hepatocyte-specific Mcl-1 knockout (KO), which causes persistent hepatocyte apoptosis. Gab1 deficiency exacerbated hepatocyte apoptosis in Mcl-1 KO mice with posttranscriptional downregulation of Bcl-XL. In BNL.CL2 cells treated with ABT-737, Gab1 knockdown posttranscriptionally suppressed Bcl-xL expression, and p35-Gab1 overexpression enhanced Bcl-xL expression. Gab1 deficiency in Mcl-1 KO mice activated STAT3 signaling in hepatocytes, increased hepatocyte proliferation, and increased the incidence of liver cancer with the exacerbation of liver fibrosis. In conclusion, Gab1 is cleaved in the presence of apoptotic stimuli and forms p35-Gab1 in hepatocytes. In chronic liver injury, the role of Gab1 in suppressing apoptosis and reducing liver damage, fibrosis, and tumorigenesis is more important than its role in liver regeneration.

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Irritable bowel syndrome: new insights into symptom mechanisms and advances in treatment

F1000Research ◽

10.12688/f1000research.7992.1 ◽

2016 ◽

Vol 5 ◽

pp. 780 ◽

Cited By ~ 15

Author(s):

Robin Spiller

Keyword(s):

Irritable Bowel Syndrome ◽

New Agents ◽

Enteric Nerves ◽

Inflammatory Bowel ◽

Magnetic Resonance Imaging Mri ◽

Irritable Bowel ◽

Fodmap Diet ◽

And Function ◽

The Impact

Despite being one of the most common conditions leading to gastroenterological referral, irritable bowel syndrome (IBS) is poorly understood. However, recent years have seen major advances. These include new understanding of the role of both inflammation and altered microbiota as well as the impact of dietary intolerances as illuminated by magnetic resonance imaging (MRI), which has thrown new light on IBS. This article will review new data on how excessive bile acid secretion mediates diarrhea and evidence from post infectious IBS which has shown how gut inflammation can alter gut microbiota and function. Studies of patients with inflammatory bowel disease (IBD) have also shown that even when inflammation is in remission, the altered enteric nerves and abnormal microbiota can generate IBS-like symptoms. The efficacy of the low FODMAP diet as a treatment for bloating, flatulence, and abdominal discomfort has been demonstrated by randomized controlled trials. MRI studies, which can quantify intestinal volumes, have provided new insights into how FODMAPs cause symptoms. This article will focus on these areas together with recent trials of new agents, which this author believes will alter clinical practice within the foreseeable future.

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Peran Pendidikan Etika Kristen dalam Media Sosial di Era Disrupsi

Jurnal Pendidikan Agama Kristen (JUPAK) ◽

10.52489/jupak.v1i1.5 ◽

2020 ◽

Vol 1 (1) ◽

pp. 38-46

Author(s):

Mesirawati Waruwu ◽

Yonatan Alex Arifianto ◽

Aji Suseno

Keyword(s):

Social Media ◽

Ethics Education ◽

Christian Ethics ◽

Christian Faith ◽

Ethical Challenges ◽

Use Of Social Media ◽

And Function ◽

Meaning And Function ◽

The Impact

The limitless development of social media, its meaning and function have begun to shift, no longer as a means of establishing relationships, communication, but at the stage of losing the role of ethics and morals, even disputes have occurred triggered by debates from communicating in social media. The purpose of this study is to describe the role of Christian ethics education in relation to the impact of social media development in the era of disruption. Using descriptive qualitative methods with literature literature can find solutions for believers in facing moral decadence due to social media abuse by knowing the era of disruption and ethical challenges from the wrong use of social media can affect moral decadence so that Christian ethics education on a biblical basis can bring modern humans. Believers in particular have become bright in social media and their use in accordance with Christian faith in this era of disruption.

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