Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence
<b>Background</b>: Treatment with the chemotherapy drug doxorubicin (DOX) may lead to toxicities that affect non-cancer cells including the liver. Supplementing the diet with creatine (Cr) has been suggested as a potential intervention to minimize DOX-induced side effects, but its effect...
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doaj-6aa29df9ce2e4c24a7756adcbbda1fb12020-12-25T00:03:20ZengMDPI AGNutrients2072-66432021-12-0113414110.3390/nu13010041Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular SenescenceNouf Aljobaily0Michael J. Viereckl1David S. Hydock2Hend Aljobaily3Tsung-Yen Wu4Raquel Busekrus5Brandon Jones6Jammie Alberson7Yuyan Han8School of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USASchool of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USASchool of Sport and Exercise Science, University of Northern Colorado, Greeley, CO 80639, USAIndependent Statistician, Fort Collins, CO 80525, USAObstetrics and Gynecology Department, University of Washington, Seattle, WA 98115, USASchool of Sport and Exercise Science, University of Northern Colorado, Greeley, CO 80639, USASchool of Sport and Exercise Science, University of Northern Colorado, Greeley, CO 80639, USASchool of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USASchool of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USA<b>Background</b>: Treatment with the chemotherapy drug doxorubicin (DOX) may lead to toxicities that affect non-cancer cells including the liver. Supplementing the diet with creatine (Cr) has been suggested as a potential intervention to minimize DOX-induced side effects, but its effect in alleviating DOX-induced hepatoxicity is currently unknown. Therefore, we aimed to examine the effects of Cr supplementation on DOX-induced liver damage. <b>Methods:</b> Male Sprague-Dawley rats were fed a diet supplemented with 2% Cr for four weeks, 4% Cr for one week followed by 2% Cr for three more weeks, or control diet for four weeks. Animals then received either a bolus i.p. injection of DOX (15 mg/kg) or saline as a placebo. Animals were then sacrificed five days-post injection and markers of hepatoxicity were analyzed using the liver-to-body weight ratio, aspartate transaminase (AST)-to- alanine aminotransferase (ALT) ratio, alkaline phosphatase (ALP), lipemia, and T-Bilirubin. In addition, hematoxylin and eosin (H&E) staining, Picro-Sirius Red staining, and immunofluorescence staining for CD45, 8-OHdG, and β-galactosidase were performed to evaluate liver morphology, fibrosis, inflammation, oxidative stress, and cellular senescence, respectively. The mRNA levels for biomarkers of liver fibrosis, inflammation, oxidative stress, and senescence-related genes were measured in liver tissues. Chromosomal stability was evaluated using global DNA methylation ELISA. <b>Results:</b> The ALT/AST ratio and liver to body weight ratio tended to increase in the DOX group, and Cr supplementation tended to attenuate this increase. Furthermore, elevated levels of liver fibrosis, inflammation, oxidative stress, and senescence were observed with DOX treatment, and Cr supplementation prior to DOX treatment ameliorated this hepatoxicity. Moreover, DOX treatment resulted in chromosomal instability (i.e., altered DNA methylation profile), and Cr supplementation showed a tendency to restore chromosomal stability with DOX treatment. <b>Conclusion:</b> The data suggest that Cr protected against DOX-induced hepatotoxicity by attenuating fibrosis, inflammation, oxidative stress, and senescence.https://www.mdpi.com/2072-6643/13/1/41liver damagedoxorubicincreatineoxidative stresssenescenceliver fibrosis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nouf Aljobaily Michael J. Viereckl David S. Hydock Hend Aljobaily Tsung-Yen Wu Raquel Busekrus Brandon Jones Jammie Alberson Yuyan Han |
spellingShingle |
Nouf Aljobaily Michael J. Viereckl David S. Hydock Hend Aljobaily Tsung-Yen Wu Raquel Busekrus Brandon Jones Jammie Alberson Yuyan Han Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence Nutrients liver damage doxorubicin creatine oxidative stress senescence liver fibrosis |
author_facet |
Nouf Aljobaily Michael J. Viereckl David S. Hydock Hend Aljobaily Tsung-Yen Wu Raquel Busekrus Brandon Jones Jammie Alberson Yuyan Han |
author_sort |
Nouf Aljobaily |
title |
Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence |
title_short |
Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence |
title_full |
Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence |
title_fullStr |
Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence |
title_full_unstemmed |
Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence |
title_sort |
creatine alleviates doxorubicin-induced liver damage by inhibiting liver fibrosis, inflammation, oxidative stress, and cellular senescence |
publisher |
MDPI AG |
series |
Nutrients |
issn |
2072-6643 |
publishDate |
2021-12-01 |
description |
<b>Background</b>: Treatment with the chemotherapy drug doxorubicin (DOX) may lead to toxicities that affect non-cancer cells including the liver. Supplementing the diet with creatine (Cr) has been suggested as a potential intervention to minimize DOX-induced side effects, but its effect in alleviating DOX-induced hepatoxicity is currently unknown. Therefore, we aimed to examine the effects of Cr supplementation on DOX-induced liver damage. <b>Methods:</b> Male Sprague-Dawley rats were fed a diet supplemented with 2% Cr for four weeks, 4% Cr for one week followed by 2% Cr for three more weeks, or control diet for four weeks. Animals then received either a bolus i.p. injection of DOX (15 mg/kg) or saline as a placebo. Animals were then sacrificed five days-post injection and markers of hepatoxicity were analyzed using the liver-to-body weight ratio, aspartate transaminase (AST)-to- alanine aminotransferase (ALT) ratio, alkaline phosphatase (ALP), lipemia, and T-Bilirubin. In addition, hematoxylin and eosin (H&E) staining, Picro-Sirius Red staining, and immunofluorescence staining for CD45, 8-OHdG, and β-galactosidase were performed to evaluate liver morphology, fibrosis, inflammation, oxidative stress, and cellular senescence, respectively. The mRNA levels for biomarkers of liver fibrosis, inflammation, oxidative stress, and senescence-related genes were measured in liver tissues. Chromosomal stability was evaluated using global DNA methylation ELISA. <b>Results:</b> The ALT/AST ratio and liver to body weight ratio tended to increase in the DOX group, and Cr supplementation tended to attenuate this increase. Furthermore, elevated levels of liver fibrosis, inflammation, oxidative stress, and senescence were observed with DOX treatment, and Cr supplementation prior to DOX treatment ameliorated this hepatoxicity. Moreover, DOX treatment resulted in chromosomal instability (i.e., altered DNA methylation profile), and Cr supplementation showed a tendency to restore chromosomal stability with DOX treatment. <b>Conclusion:</b> The data suggest that Cr protected against DOX-induced hepatotoxicity by attenuating fibrosis, inflammation, oxidative stress, and senescence. |
topic |
liver damage doxorubicin creatine oxidative stress senescence liver fibrosis |
url |
https://www.mdpi.com/2072-6643/13/1/41 |
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