Acrolein contributes to urothelial carcinomas in patients with chronic kidney disease

Hong, Jian‐Hua; Lee, Priscilla Ann Hweek; Lu, Yongjun; Huang, Cheng; Chen, Chung‐Hsin; Chiang, Chiao–Hsi; Chow, Po Ming; Jaw, Fu Shan; Wang, Chung Chieh; Huang, Chao Yuan; Wang, Tse Wen; Liu, Jin Hui; Wang, Hsiang Tsui

doi:10.1016/j.urolonc.2020.02.017

Cited by 14 publications

(13 citation statements)

References 29 publications

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“…In animal models of CKD, acrolein induced dyslipidemia and cardiac damage [ 100 ], and acrolein in concentrations as low as 5 µM inhibited cell culture growth by 50% [ 101 ]. It should also be noted that serum levels of acrolein are elevated in CKD patients and it has been suggested that acrolein should formally be considered a uremic toxin [ 96 , 102 ].…”

Section: Pbut Derivation and Pathological Mechanismsmentioning

confidence: 99%

Gut-Derived Protein-Bound Uremic Toxins

Graboski

Redinbo

2020

Toxins

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Chronic kidney disease (CKD) afflicts more than 500 million people worldwide and is one of the fastest growing global causes of mortality. When glomerular filtration rate begins to fall, uremic toxins accumulate in the serum and significantly increase the risk of death from cardiovascular disease and other causes. Several of the most harmful uremic toxins are produced by the gut microbiota. Furthermore, many such toxins are protein-bound and are therefore recalcitrant to removal by dialysis. We review the derivation and pathological mechanisms of gut-derived, protein-bound uremic toxins (PBUTs). We further outline the emerging relationship between kidney disease and gut dysbiosis, including the bacterial taxa altered, the regulation of microbial uremic toxin-producing genes, and their downstream physiological and neurological consequences. Finally, we discuss gut-targeted therapeutic strategies employed to reduce PBUTs. We conclude that targeting the gut microbiota is a promising approach for the treatment of CKD by blocking the serum accumulation of PBUTs that cannot be eliminated by dialysis.

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Section: Pbut Derivation and Pathological Mechanismsmentioning

confidence: 99%

Gut-Derived Protein-Bound Uremic Toxins

Graboski

Redinbo

2020

Toxins

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“…Acrolein conjugates with glutathione within the liver and is excreted in the urine as mercapturic acid metabolites (Stevens & Maier, 2008). Different direct mechanisms for acrolein toxicity have been suggested including DNA damage, inhibition of DNA repair (Hong et al, 2020) and protein adduction. Indirect mechanisms such as oxidative stress, impairment of mitochondrial function and endoplasmic reticulum stress, cell membrane damage, and inflammation which affects different organs of the body were also reported in the literature (Moghe et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

N‐acetylcysteine is more effective than ellagic acid in preventing acrolein induced dysfunction in mitochondria isolated from rat liver

2021

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Acrolein, a common environmental, food, and water pollutant, has been linked to the pathology of several diseases. This toxic substance is an unsaturated aldehyde and a major component of cigarette smoke and also produced during the processing of fat‐containing foods. This study aimed to evaluate the protective effect of ellagic acid and N‐acetylcysteine (NAC) in acrolein‐induced toxicity in mitochondria isolated from the rat liver. The mitochondria were exposed to different concentrations of acrolein for 40 min, then functionality was assessed. Contact with acrolein rapidly and remarkably depleted the intracellular glutathione and antioxidant capacity, because of increased ROS production and lipid peroxidation which may lead to the cell death. Mitochondria were then pre‐exposed to different concentrations of ellagic acid, NAC, and IC50 concentration of acrolein. Consistent with the results, acrolein decreased GSH content and increased ROS level and lipid peroxidation, which led to ATP depletion and mitochondrial dysfunction. While ellagic acid has been able to reduce ROS and therefore the permeability of the mitochondrial membrane potential (MMP), presumably via its antioxidant properties, we've not detected its favorable effect on GSH and ATP restoration and also on mitochondrial complex II function. However, NAC strongly decreased ROS, lipid peroxidation and MMP and improved GSH content and complex II activity. These results showed that ellagic acid while reported to possess some cellular protective properties, did not prevent mitochondria from being affected by acrolein during this in vitro study. Practical applications Ellagic acid is found in fruits, vegetables, and nuts which are revealed to possess strong antioxidant and protective properties. Mitochondrial dysfunction has been implicated in the pathogenesis of some chronic diseases including cancer, diabetes, liver disease, and neurodegenerative disorders, and presumably, ellagic acid by its mitochondrial protective effects can be helpful in these chronic conditions. Acrolein is an α,β‐unsaturated aldehyde that can be produced during cooking at high temperature. By increasing the ROS level and lipid peroxidation and depleting the glutathione content, acrolein induces cellular damage and mitochondrial toxicity. This toxicant is taken into account as a carcinogen and mutagen. In this study, the protective effect of ellagic acid in comparison with N‐acetylcysteine has been investigated during the toxicity of acrolein in the rat liver mitochondria to look for evidence of whether it is useful or not through this insult.

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“…We measured urinary acrolein exposures in our study because acrolein initiates bladder cancer in rodents, transforms human urothelial cells in vitro, and leads to DNA adducts that are over-represented in human urothelial carcinomas compared to normal bladder tissue. [29][30][31] Exposure to acrolein was measured as its stable metabolite 3-HPMA. 32 Levels detected in humans in our study (median 280 ng/mL, unadjusted for creatinine) were comparable to those previously reported in non-smokers (219-420 ng/mL).…”

Section: Discussionmentioning

confidence: 99%