Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence

Background: 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. Methods: 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. Results: 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. Conclusion: The data suggest that Cr protected against DOX-induced hepatotoxicity by attenuating fibrosis, inflammation, oxidative stress, and senescence.

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Effects ofBauhinia forficataTea on Oxidative Stress and Liver Damage in Diabetic Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/8902954 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 19

Author(s):

Andréia Caroline Fernandes Salgueiro ◽

Vanderlei Folmer ◽

Marianne Pires da Silva ◽

Andreas Sebastian Loureiro Mendez ◽

Ana Paula Pegoraro Zemolin ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Body Weight ◽

Liver Damage ◽

Weight Ratio ◽

Protein Carbonyl ◽

Diabetic Mice ◽

Body Weight Ratio ◽

Glucose Levels ◽

Nonprotein Thiols

This study was designed to evaluate the effects ofBauhinia forficataLink subsp.pruinosa(BF) tea on oxidative stress and liver damage in streptozotocin (STZ)-induced diabetic mice. Diabetic male mice have remained 30 days without any treatment. BF treatment started on day 31 and continued for 21 days as a drinking-water substitute. We evaluated (1) BF chemical composition; (2) glucose levels; (3) liver/body weight ratio and liver transaminases; (4) reactive oxygen species (ROS), lipid peroxidation, and protein carbonylation in liver; (5) superoxide dismutase (SOD) and catalase (CAT) activities in liver; (6)δ-aminolevulinate dehydratase (δ-ALA-D) and nonprotein thiols (NPSH) in liver; (7) Nrf2, NQO-1, and HSP70 levels in liver and pancreas. Phytochemical analyses identified four phenols compounds. Diabetic mice present high levels of NQO-1 in pancreas, increased levels of ROS and lipid peroxidation in liver, and decrease in CAT activity. BF treatment normalized all these parameters. BF did not normalize hyperglycemia, liver/body weight ratio, aspartate aminotransferase, protein carbonyl, NPSH levels, andδ-ALA-D activity. The raised oxidative stress seems to be a potential mechanism involved in liver damage in hyperglycemic conditions. Our results indicated that BF protective effect could be attributed to its antioxidant capacity, more than a hypoglycemic potential.

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Age-associated increase in rat ventricular ANP gene expression correlates with cardiac hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.3.h1003 ◽

1995 ◽

Vol 269 (3) ◽

pp. H1003-H1008 ◽

Cited By ~ 5

Author(s):

A. Younes ◽

M. O. Boluyt ◽

L. O'Neill ◽

A. L. Meredith ◽

M. T. Crow ◽

...

Keyword(s):

Gene Expression ◽

Body Weight ◽

Cardiac Hypertrophy ◽

Left Atrial ◽

Northern Blot Analysis ◽

Weight Ratio ◽

Left Ventricular ◽

Mrna Levels ◽

Body Weight Ratio ◽

Old Rats

Atrial natriuretic peptide (ANP), a cardiac-specific hormone, is stored in the atria and released in response to atrial stretch. During cardiac hypertrophy, ANP gene expression is markedly upregulated in the left ventricle (LV). Because the hearts of normotensive senescent rats exhibit left atrial (LA) and left ventricular (LV) hypertrophy and dilatation, we examined ANP mRNA levels by Northern blot analysis and ANP peptide concentrations by radioimmunoassay in atria, LVs, and plasma of rats at 2, 6, 18, and 22-24 mo of age. Compared with LVs of 6-mo-old rats, the LV-to-body weight ratio was elevated 30% by 18 mo of age, whereas levels of ANP mRNA were elevated twofold (not significant) and sevenfold (P < 0.05) in the LV of 18- and 22- to 24-mo-old rats, respectively. The concentration of immunoreactive ANP (ir-ANP) exhibited a four- to fivefold increase in LVs of 18- and 22- to 24-mo-old rats compared with values for 6-mo-old rats (43 +/- 4 pmol/g wet wt; means +/- SE). Among 18-and 22- to 24-mo-old rats a significant correlation was observed between ANP peptide concentration and LV hypertrophy (r 2 = 0.64). Levels of ANP mRNA and ir-ANP in the atria exhibited only modest changes with aging.(ABSTRACT TRUNCATED AT 250 WORDS)

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Lipoic Acid Exacerbates Oxidative Stress and Lipid Accumulation in the Liver of Wistar Rats Fed a Hypercaloric Choline-Deficient Diet

Nutrients ◽

10.3390/nu13061999 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1999

Author(s):

Lidia V. Kravchenko ◽

Ilya V. Aksenov ◽

Nikolay S. Nikitin ◽

Galina V. Guseva ◽

Ludmila I. Avrenyeva ◽

...

Keyword(s):

Oxidative Stress ◽

Body Weight ◽

Liver Disease ◽

Lipoic Acid ◽

Lipid Accumulation ◽

Wistar Rats ◽

Weight Ratio ◽

Body Weight Ratio ◽

Deficient Diet ◽

Male Wistar Rats

Non-alcoholic fatty liver disease (NAFLD) is currently estimated as the most prevalent chronic liver disease in all age groups. An increasing body of evidence obtained in experimental and clinical data indicates that oxidative stress is the most important pathogenic factor in the development of NAFLD. The study aimed to investigate the impact of α-lipoic acid (LA), widely used as an antioxidant, on the effects of a hypercaloric choline-deficient diet. Male Wistar rats were divided into three groups: control diet (C); hypercaloric choline-deficient diet (HCCD), and hypercaloric choline-deficient diet with α-lipoic acid (HCCD+LA). Supplementation of HCCD with LA for eight weeks led to a decrease in visceral adipose tissue/body weight ratio, the activity of liver glutathione peroxidase and paraoxonase-1, plasma, and liver total antioxidant activity, as well as an increase in liver/body weight ratio, liver total lipid and triglyceride content, and liver transaminase activities compared to the HCCD group without LA. In conclusion, our study shows that α-lipoic acid detains obesity development but exacerbates the severity of diet-induced oxidative stress and lipid accumulation in the liver of male Wistar rats fed a hypercaloric choline-deficient diet.

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Angiotensin II in cardiac pressure-overload hypertrophy in fetal sheep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.6.r2037 ◽

2001 ◽

Vol 281 (6) ◽

pp. R2037-R2047 ◽

Cited By ~ 24

Author(s):

Jeffrey L. Segar ◽

Gregory B. Dalshaug ◽

Kurt A. Bedell ◽

Oliva M. Smith ◽

Thomas D. Scholz

Keyword(s):

Blood Pressure ◽

Body Weight ◽

Weight Ratio ◽

Pressure Overload ◽

Mrna Levels ◽

Ang Ii ◽

Body Weight Ratio ◽

Fetal Sheep ◽

Arterial Blood ◽

Selective Increase

We previously demonstrated in fetal sheep that blockade of ANG II type 1 (AT1) receptors did not attenuate an increase in right ventricle (RV) mass resulting from partial occlusion of the pulmonary artery (PA). We have now determined the effects of AT2-receptor blockade (PD-123319, 10 mg · kg−1· day−1continuous iv) on the response of the fetal RV to PA banding for 7 days. Four groups of fetuses (each n = 7) were studied beginning at 126 ± 1 days gestation (term 145 days). RV weight-to-body weight ratio (RV wt/body wt) increased ( P < 0.05) in PA-banded (6.00 ± 0.09 g/kg) and PA-banded + PD-123319 (6.19 ± 0.27 g/kg) compared with control (5.17 ± 0.17 g/kg) and PD-123319-infused (5.27 ± 0.35 g/kg) fetuses (means ± SE). Blood pressure and heart rate were similar in all groups. PD-123319 produced a decrease ( P < 0.05) in AT1but not AT2mRNA levels in both fetal ventricles. To examine the effect of ANG II on fetal heart growth, twin fetal sheep were infused with either ANG II (twin received vehicle) or phenylephrine (Phe) (twin received vehicle) continuously for 7 days. Mean arterial blood pressure was 20–25 mmHg higher in ANG II and Phe fetuses compared with controls. The rate-pressure product was similar in ANG II and Phe fetuses and 40–50% greater than controls. Phe resulted in no change in RV wt/body wt or left ventricle-to-body weight ratio (LV wt/body wt) compared with controls. In contrast, ANG II produced a selective increase (27 ± 5%, P < 0.05) in LV wt/body wt; no effect was seen on the RV. ANG II produced a decrease ( P < 0.05) in LV but not RV AT1mRNA levels compared with controls; no effect was seen with Phe. The data demonstrate that in the ovine fetus, AT2receptors do not contribute to the maintenance of blood pressure or the development of pressure-overload RV hypertrophy. Elevated ANG II levels produce a selective increase in LV mass in the fetal sheep that is, in part, independent of increased systolic load.

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Effect of taxifolin/dapagliflozin combination on colistin-induced nephrotoxicity in rats

Human & Experimental Toxicology ◽

10.1177/09603271211010906 ◽

2021 ◽

pp. 096032712110109

Author(s):

AM Kabel ◽

SA Salama

Keyword(s):

Oxidative Stress ◽

Body Weight ◽

Growth Factor ◽

Weight Ratio ◽

Nuclear Factor ◽

Body Weight Ratio ◽

Kidney Weight ◽

Oxidative Stress Parameters ◽

Tgf Β1 ◽

Stress Parameters

Colistin is an antimicrobial agent that is used in resistant gram-negative infections. Its most common dose-limiting adverse effect is nephrotoxicity. The objective of our study was to explore the possible effects of each of taxifolin and dapagliflozin alone and in combination on colistin-induced nephrotoxicity in rats. Sixty male rats were randomized into six groups: Control; colistin; colistin + taxifolin; colistin + dapagliflozin; colistin + carboxymethyl cellulose (CMC) and colistin + taxifolin + dapagliflozin. Dapagliflozin, taxifolin, and CMC were given daily for 7 days, 4 hours before colistin injection. Kidney weight/body weight ratio and renal function tests were determined. Renal tissue nerve growth factor-β (NGF-β), transforming growth factor beta 1 (TGF-β1), proinflammatory cytokines, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB) p65, signal transducer and activator of transcription 3 (STAT3), oxidative stress parameters, beclin-1 and c-Jun NH2-terminal kinase (JNK) activities were measured. Kidneys were examined histopathologically and immunohistochemically. Taxifolin and/or dapagliflozin induced significant improvement in the renal functions and oxidative stress parameters with significant increase in tissue Nrf2, STAT3 and NGF-β accompanied with significant decrease in kidney weight/body weight ratio, tissue proinflammatory cytokines, TGF-β1, NF-κB (p65), TLR4, beclin-1 and JNK activities and improved the histopathological picture when compared to rats treated with colistin alone. This improvement was significant with taxifolin/dapagliflozin combination compared to rats treated with each of these agents alone. So, we concluded that the combined use of taxifolin and dapagliflozin may confer a therapeutic tool for attenuation of colistin-induced nephrotoxicity.

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Cardiac hypertrophy associated with impaired regulation of cardiac ryanodine receptor by calmodulin and S100A1

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00144.2013 ◽

2013 ◽

Vol 305 (1) ◽

pp. H86-H94 ◽

Cited By ~ 21

Author(s):

Naohiro Yamaguchi ◽

Asima Chakraborty ◽

Tai-Qin Huang ◽

Le Xu ◽

Angela C. Gomez ◽

...

Keyword(s):

Body Weight ◽

Amino Acid ◽

Atrial Natriuretic Peptide ◽

Cardiac Hypertrophy ◽

Cardiac Function ◽

Ryanodine Receptor ◽

Weight Ratio ◽

Heart Weight ◽

Mrna Levels ◽

Body Weight Ratio

The cardiac ryanodine receptor (RyR2) is inhibited by calmodulin (CaM) and S100A1. Simultaneous substitution of three amino acid residues (W3587A, L3591D, F3603A; RyR2ADA) in the CaM binding domain of RyR2 results in loss of CaM inhibition at submicromolar (diastolic) and micromolar (systolic) Ca2+, cardiac hypertrophy, and heart failure in Ryr2 ADA/ADA mice. To address whether cardiac hypertrophy results from the elimination of CaM and S100A1 inhibition at diastolic or systolic Ca2+, a mutant mouse was generated with a single RyR2 amino acid substitution (L3591D; RyR2D). Here we report that in single-channel measurements RyR2-L3591D isolated from Ryr2 D/D hearts lost CaM inhibition at diastolic Ca2+ only, whereas S100A1 regulation was eliminated at both diastolic and systolic Ca2+. In contrast to the ∼2-wk life span of Ryr2 ADA/ADA mice, Ryr2 D/D mice lived longer than 1 yr. Six-month-old Ryr2 D/D mice showed a 9% increase in heart weight-to-body weight ratio, modest changes in cardiac morphology, and a twofold increase in atrial natriuretic peptide mRNA levels compared with wild type. After 4-wk pressure overload with transverse aortic constriction, heart weight-to-body weight ratio and atrial natriuretic peptide mRNA levels increased and echocardiography showed changes in heart morphology of Ryr2 D/D mice compared with sham-operated mice. Collectively, the findings indicate that the single RyR2-L3591D mutation, which distinguishes the effects of diastolic and systolic Ca2+, alters heart size and cardiac function to a lesser extent in Ryr2 D/D mice than the triple mutation in Ryr2 ADA/ADA mice. They further suggest that CaM inhibition of RyR2 at systolic Ca2+ is important for maintaining normal cardiac function.

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Apigenin protects mice against 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced cholestasis

Food & Function ◽

10.1039/d0fo02910f ◽

2021 ◽

Vol 12 (5) ◽

pp. 2323-2334

Author(s):

Shihong Zheng ◽

Peichang Cao ◽

Zequn Yin ◽

Xuerui Wang ◽

Yuanli Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Metabolism ◽

Liver Fibrosis ◽

Liver Damage ◽

Liver Diseases ◽

Potential Drug ◽

Abnormal Lipid Metabolism ◽

And Oxidative Stress

Apigenin prevented the DDC-induced abnormal lipid metabolism, liver damage and liver fibrosis by reducing inflammation and oxidative stress. Apigenin might be a potential drug for the treatment of cholestatic liver diseases.

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Exercise and clenbuterol as strategies to decrease the progression of muscular dystrophy in mdx mice

Journal of Applied Physiology ◽

10.1152/jappl.1996.80.3.734 ◽

1996 ◽

Vol 80 (3) ◽

pp. 734-741 ◽

Cited By ~ 24

Author(s):

E. E. Dupont-Versteegden

Keyword(s):

Body Weight ◽

Muscular Dystrophy ◽

Weight Ratio ◽

Morphological Characteristics ◽

Mdx Mice ◽

Body Weight Ratio ◽

Muscle Weight ◽

Sedentary Group ◽

Running Activity ◽

Tetanic Tension

The effects of exercise and the combination of exercise and clenbuterol on progression of muscular dystrophy were studied in mdx mice. At 3 wk of age, mdx mice were randomly assigned to sedentary (MS), exercise (ME), or combined exercise and clenbuterol (MEC) groups. Clenbuterol was given in the drinking water (1.0-1.5 mg . kg body weight-1 . day-1), and exercise consisted of spontaneous running activity on exercise wheels. At 3 mo or 1 yr of age, ventilatory function, contractile properties, and morphological characteristics of the soleus (Sol) and diaphragm (Dia) muscles were measured. The mdx mice receiving clenbuterol ran less than the mice without clenbuterol. The combination of clenbuterol and exercise was associated with an increase in Sol muscle weight and a muscle weight-to-body weight ratio of 30-35% compared with the sedentary group and approximately 20% compared to exercise alone. Myosin and total protein concentrations of the Sol and Dia increased in the MEC group at 1 yr of age only. Normalized active tension was increased in the Dia at 1 yr of age in both the ME and MEC groups by approximately 30%. Absolute tetanic tension of the Sol was increased at both 3 mo and 1 yr of age in the MEC compared with the MS group. At 1 yr of age, there was an additional 23% increase compared with the ME group. Fatigability increased in the MEC group by approximately 25% in the Sol and Dia muscles at both ages compared with the MS and ME groups. Results indicate that exercise and exercise plus clenbuterol decrease the progression of muscular dystrophy. However, different mechanisms may be involved because the combination of clenbuterol and exercise resulted in increased fatigability and the development of deformities, whereas exercise alone did not. Therefore, clenbuterol may not be suitable for use in patients with muscular dystrophy.

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A study on the safety evaluation of buphrenorphine administered through an autoinjector compared with manual injection using haematological and biochemical variables in rats

Human & Experimental Toxicology ◽

10.1177/0960327116674528 ◽

2016 ◽

Vol 36 (9) ◽

pp. 901-909 ◽

Cited By ~ 1

Author(s):

D Sheela ◽

R Vijayaraghavan ◽

S Senthilkumar

Keyword(s):

Body Weight ◽

Research Work ◽

Safety Evaluation ◽

Weight Ratio ◽

The Body ◽

Control Group ◽

Body Weight Ratio ◽

Significant Difference ◽

Manual Group ◽

Significant Change

Buprenorphine drug cartridge was made for autoinjector device for use in emergency and critical situations to reduce the morbidity and mortality. Water-filled cartridges were prepared and buprenorphine was injected aseptically in the cartridge, to make 0.05 and 0.10 mg/mL. Rats were injected intraperitoneally, buprenorphine (0.3 and 0.6 mg/kg), repeatedly with the autoinjector and compared with manual injection (7 days and 14 days) using various haematological and biochemical parameters. No significant change was observed in the body weight, organ to body weight ratio and haematological variables in any of the experimental groups compared with the control group. Except serum urea and aspartate aminotransferase, no significant change was observed in glucose, cholesterol, triglycerides, bilirubin, protein, albumin, creatinine, uric acid, alanine aminotransferase, gamma glutamyltransferase and alkaline phosphatase. The autoinjectors deliver the drugs with spray effect and force for faster absorption. In the present study, the autoinjector meant for intramuscular injection was injected intraperitoneally in rats, and the drug was delivered with force on the vital organs. No significant difference was observed in the autoinjector group compared to the manual group showing tolerability and safety of the buphrenorphine autoinjector. This study shows that buprenorphine autoinjector can be considered for further research work.

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