Effects of p-Cresol on Oxidative Stress, Glutathione Depletion, and Necrosis in HepaRG Cells: Comparisons to Other Uremic Toxins and the Role of p-Cresol Glucuronide Formation

The toxicological effects of p-cresol have primarily been attributed to its metabolism products; however, very little human data are available in the key organ (i.e., liver) responsible for the generation of these metabolites. Experiments were conducted in HepaRG cells utilizing the following markers of cellular toxicity: 2′-7′-dichlorofluorescein (DCF; oxidative stress) formation, total cellular glutathione (GSH) concentration, and lactate dehydrogenase (LDH; cellular necrosis) release. Concentrations of p-cresol, p-cresol sulfate, and p-cresol glucuronide were determined using validated assays. p-Cresol exposure resulted in concentration- and time-dependent changes in DCF (EC50 = 0.64 ± 0.37 mM at 24 h of exposure) formation, GSH (EC50 = 1.00 ± 0.07 mM) concentration, and LDH (EC50 = 0.85 ± 0.14 mM) release at toxicologically relevant conditions. p-Cresol was also relatively more toxic than 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, indole-3-acetic acid, indoxyl sulfate, kynurenic acid, and hippuric acid on all markers. Although the exogenous administration of p-cresol sulfate and p-cresol glucuronide generated high intracellular concentrations of these metabolites, both metabolites were less toxic compared to p-cresol at equal-molar conditions. Moreover, p-cresol glucuronide was the predominant metabolite generated in situ from p-cresol exposure. Selective attenuation of glucuronidation (without affecting p-cresol sulfate formation, while increasing p-cresol accumulation) using independent chemical inhibitors (i.e., 0.75 mM l-borneol, 75 µM amentoflavone, or 100 µM diclofenac) consistently resulted in further increases in LDH release associated with p-cresol exposure (by 28.3 ± 5.3%, 30.0 ± 8.2% or 27.3 ± 6.8%, respectively, compared to p-cresol treatment). These novel data indicated that p-cresol was a relatively potent toxicant, and that glucuronidation was unlikely to be associated with the manifestation of its toxic effects in HepaRG cells.

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Pivotal role of glutathione depletion in plasma-induced endothelial oxidative stress during sepsis

Critical Care Medicine ◽

10.1097/ccm.0b013e3181800387 ◽

2008 ◽

Vol 36 (8) ◽

pp. 2328-2334 ◽

Cited By ~ 22

Author(s):

Olivier Huet ◽

Christaine Cherreau ◽

Carole Nicco ◽

Laurent Dupic ◽

Marc Conti ◽

...

Keyword(s):

Oxidative Stress ◽

Pivotal Role ◽

Glutathione Depletion

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An Increasing Role of Polyphenols as Novel Therapeutics for Alzheimer’s: A Review

Medicinal Chemistry ◽

10.2174/1573406415666191105154407 ◽

2020 ◽

Vol 16 (8) ◽

pp. 1007-1021 ◽

Cited By ~ 2

Author(s):

Nasiara Karim ◽

Haroon Khan ◽

Imran Khan ◽

Ouyang Guo ◽

Eduardo Sobarzo-Sánchez ◽

...

Keyword(s):

Oxidative Stress ◽

Natural Products ◽

Immune Responses ◽

Cognitive Deficits ◽

Neurodegenerative Disorder ◽

Therapeutic Agents ◽

Pharmacological Interventions ◽

Stress Formation ◽

Molecular Aspects

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, with approximately 29 million older people suffering from this disease worldwide. This number is expected to become triple by 2050. AD is a complex and multifactorial neurodegenerative condition, characterized by complex pathology including oxidative stress, formation of aggregates of amyloid and tau, enhanced immune responses, metal deposition and disturbances in cholinesterase enzymes. There is no effective pharmacological treatment for combating the disease to date. The ineffectiveness of current pharmacological interventions in AD has led scientists to search for more safe and effective alternative therapeutic agents. Thus, natural products have become an important avenue for drug discovery in AD research. In this regard, polyphenols are natural products that have been shown to be effective in the modulation of the type of neurodegenerative changes seen in AD, suggesting a possible therapeutic role. The present review focuses on the chemistry of polyphenols, clinical studies for evaluating polyphenols as effective alternatives in AD treatment, cellular and molecular aspects of polyphenols in improving cognitive deficits and the current challenges and futuristic approaches to use polyphenols as safe and effective therapeutic agents in AD treatment.

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Copper doping enhanced the oxidative stress–mediated cytotoxicity of TiO2 nanoparticles in A549 cells

Human & Experimental Toxicology ◽

10.1177/0960327117714040 ◽

2017 ◽

Vol 37 (5) ◽

pp. 496-507 ◽

Cited By ~ 8

Author(s):

J Ahmad ◽

MA Siddiqui ◽

MJ Akhtar ◽

HA Alhadlaq ◽

A Alshamsan ◽

...

Keyword(s):

Oxidative Stress ◽

Environmental Remediation ◽

Titanium Dioxide Nanoparticles ◽

Reactive Oxygen Species Generation ◽

A549 Cells ◽

Glutathione Depletion ◽

Dependent Manner ◽

Cu Doping ◽

And Oxidative Stress

Physicochemical properties of titanium dioxide nanoparticles (TiO2 NPs) can be tuned by doping with metals or nonmetals. Copper (Cu) doping improved the photocatalytic behavior of TiO2 NPs that can be applied in various fields such as environmental remediation and nanomedicine. However, interaction of Cu-doped TiO2 NPs with human cells is scarce. This study was designed to explore the role of Cu doping in cytotoxic response of TiO2 NPs in human lung epithelial (A549) cells. Characterization data demonstrated the presence of both TiO2 and Cu in Cu-doped TiO2 NPs with high-quality lattice fringes without any distortion. The size of Cu-doped TiO2 NPs (24 nm) was lower than pure TiO2 NPs (30 nm). Biological results showed that both pure and Cu-doped TiO2 NPs induced cytotoxicity and oxidative stress in a dose-dependent manner. Low mitochondrial membrane potential and higher caspase-3 enzyme (apoptotic markers) activity were also observed in A549 cells exposed to pure and Cu-doped TiO2 NPs. We further observed that cytotoxicity caused by Cu-doped TiO2 NPs was higher than pure TiO2 NPs. Moreover, antioxidant N-acetyl cysteine effectively prevented the reactive oxygen species generation, glutathione depletion, and cell viability reduction caused by Cu-doped TiO2 NPs. This is the first report showing that Cu-doped TiO2 NPs induced cytotoxicity and oxidative stress in A549 cells. This study warranted further research to explore the role of Cu doping in toxicity mechanisms of TiO2 NPs.

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Reestablishment of Ischemia-Reperfusion Liver Injury by N-Acetylcysteine Administration prior to a Preconditioning Iron Protocol

The Scientific World JOURNAL ◽

10.1155/2013/607285 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Virginia Fernández ◽

Romina Vargas ◽

Valentina Castillo ◽

Nicolás Cádiz ◽

Daniela Bastías ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Ischemia Reperfusion ◽

Protein Carbonyl ◽

Glutathione Depletion ◽

Sprague Dawley ◽

Short Term ◽

Sprague Dawley Rats ◽

Hepatic Histology

The role of iron (Fe)-induced prooxidant status in Fe preconditioning against ischemia (1 h)-reperfusion (20 h) induced liver injury was assessed using N-acetylcysteine (NAC) (1 g/kg) before Fe (50 mg/kg), given to male Sprague Dawley rats on alternate days during 10 days. IR significantly increased serum aspartate transaminase (AST) and alanine transaminase (ALT) levels, with drastic changes in liver histology, hepatic glutathione depletion, and nuclear factor-κB (NF-κB) p65 diminution (P<0.05) (ELISA). Fe-induced liver oxidative stress, as evidenced by higher protein carbonyl/glutathione content ratios (P<0.05) at days 11 and 12 after treatment, was abolished by NAC. Under these conditions, short-term Fe administration exerted significant protection against IR liver injury, as shown by 85% and 60% decreases in IR-induced serum AST and ALT (P<0.05), respectively, and normalization of hepatic histology, glutathione levels, and NF-κB activation, changes that were suppressed by NAC administration prior to Fe. Results of this study indicate that NAC administration prior to an iron protocol reestablishes IR liver injury, supporting the role of Fe-induced transient oxidative stress in hepatoprotection and its potential clinical application.

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The role of oxidative stress in the toxicity of pyridoxal isonicotinoyl hydrazone (PIH) analogues

Biochemical Society Transactions ◽

10.1042/bst0300755 ◽

2002 ◽

Vol 30 (4) ◽

pp. 755-758 ◽

Cited By ~ 15

Author(s):

J. L. Buss ◽

J. Neuzil ◽

P. Ponka

Keyword(s):

Oxidative Stress ◽

K562 Cells ◽

Redox Status ◽

Jurkat Cells ◽

Glutathione Depletion ◽

Pyridoxal Isonicotinoyl Hydrazone ◽

Fe Complexes

Pyridoxal isonicotinoyl hydrazone (PIH) analogues are effective iron chelators in vivo and in vitro, and may be of value for the treatment of secondary iron overload. The sensitivity of Jurkat cells to Fe-chelator complexes was enhanced several-fold by the depletion of the antioxidant glutathione, indicating the role of oxidative stress in their toxicity. K562 cells loaded with eicosapentaenoic acid, a fatty acid particularly susceptible to oxidation, were also more sensitive to the toxic effects of the Fe complexes, and toxicity was proportional to lipid peroxidation. Thus Fechelator complexes cause oxidative stress, which may be a major component of their toxicity. As was the case for their Fe complexes, the toxicity of PIH analogues was enhanced by glutathione depletion of Jurkat cells and eicosapentaenoic acidloading of K562 cells. Thus the toxicity of the chelators themselves is also enhanced by compromised cellular redox status. In addition, the toxicity of the chelators was diminished by culturing Jurkat cells under hypoxic conditions, which may limit the production of the reactive oxygen species that initiate oxidative stress. A significant part of the toxicity of the chelators may be due to intracellular formation of Fe-chelator complexes, which oxidatively destroy the cell.

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A multilayered repair system protects the mycobacterial chromosome from endogenous and antibiotic-induced oxidative damage

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2006792117 ◽

2020 ◽

Vol 117 (32) ◽

pp. 19517-19527

Author(s):

Pierre Dupuy ◽

Mir Howlader ◽

Michael S. Glickman

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Dna Polymerases ◽

Repair System ◽

Genomic Integrity ◽

Chromosomal Dna ◽

Living Organisms ◽

Oxidative Damage To Dna

Oxidative damage to DNA is a threat to the genomic integrity and coding accuracy of the chromosomes of all living organisms. Guanine is particularly susceptible to oxidation, and 8-oxo-dG (OG), when produced in situ or incorporated by DNA polymerases, is highly mutagenic due to mispairing with adenine. In many bacteria, defense against OG depends on MutT enzymes, which sanitize OG in the nucleotide pool, and the MutM/Y system, which counteracts OG in chromosomal DNA. InEscherichia coli, antibiotic lethality has been linked to oxidative stress and the downstream consequences of OG processing. However, in mycobacteria, the role of these systems in genomic integrity and antibiotic lethality is not understood, in part because mycobacteria encode four MutT enzymes and two MutMs, suggesting substantial redundancy. Here, we definitively probe the role of OG handling systems in mycobacteria. We find that, although MutT4 is the only MutT enzyme required for resistance to oxidative stress, this effect is not due to OG processing. We find that the dominant system that defends against OG-mediated mutagenesis is MutY/MutM1, and this system is dedicated to in situ chromosomal oxidation rather than correcting OG incorporated by accessory polymerases (DinB1/DinB2/DinB3/DnaE2). In addition, we uncover that mycobacteria resist antibiotic lethality through nucleotide sanitization by MutTs, and in the absence of this system, accessory DNA polymerases and MutY/M contribute to antibiotic-induced lethality. These results reveal a complex, multitiered system of OG handling in mycobacteria with roles in oxidative stress resistance, mutagenesis, and antibiotic lethality.

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