Galangin Activates Nrf2 Signaling and Attenuates Oxidative Damage, Inflammation, and Apoptosis in a Rat Model of Cyclophosphamide-Induced Hepatotoxicity

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Abstract

Cyclophosphamide (CP) is a widely used chemotherapeutic agent; however, its clinical application is limited because of its multi-organ toxicity. Galangin (Gal) is a bioactive flavonoid with promising biological activities. This study investigated the hepatoprotective effect of Gal in CP-induced rats. Rats received Gal (15, 30 and 60 mg/kg/day) for 15 days followed by a single dose of CP at day 16. Cyclophosphamide triggered liver injury characterized by elevated serum transaminases, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), and histopathological manifestations. Increased hepatic reactive oxygen species, malondialdehyde, nitric oxide, and oxidative DNA damage along with declined glutathione and antioxidant enzymes were demonstrated in CP-administered rats. CP provoked hepatic nuclear factor-kappaB (NF-κB) phosphorylation and increased mRNA abundance of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) both expression and serum levels. Gal prevented CP-induced liver injury, boosted antioxidants and suppressed oxidative stress, DNA damage, NF-κB phosphorylation and pro-inflammatory mediators. Gal diminished Bax and caspase-3, and increased B-cell lymphoma-2 (Bcl-2) in liver of CP-administered rats. In addition, Gal increased peroxisome proliferator-activated receptor gamma (PPARγ) expression and activated hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) signaling showed by the increase in Nrf2, NAD(P)H: quinone acceptor oxidoreductase-1 (NQO-1) and heme oxygenase 1 (HO-1) in CP-administered rats. These findings suggest that Gal prevents CP hepatotoxicity through activation of Nrf2/HO-1 signaling and attenuation of oxidative damage, inflammation and cell death. Therefore, Gal might represent a promising adjuvant therapy to prevent hepatotoxicity in patients on CP treatment.

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PPARγ and Oxidative Stress: Con(β) Catenating NRF2 and FOXO

Simone Polvani, Mirko Tarocchi, Andrea Galli (2012)

Peroxisome-proliferator activator receptor γ (PPARγ) is a nuclear receptor of central importance in energy homeostasis and inflammation. Recent experimental pieces of evidence demonstrate that PPARγ is implicated in the oxidative stress response, an imbalance between antithetic prooxidation and antioxidation forces that may lead the cell to apoptotic or necrotic death. In this delicate and intricate game of equilibrium, PPARγ stands out as a central player devoted to the quenching and containment of the damage and to foster cell survival. However, PPARγ does not act alone: indeed the nuclear receptor is at the point of interconnection of various pathways, such as the nuclear factor erythroid 2-related factor 2 (NRF2), Wnt/β-catenin, and forkhead box proteins O (FOXO) pathways. Here we reviewed the role of PPARγ in response to oxidative stress and its interaction with other signaling pathways implicated in this process, an interaction that emerged as a potential new therapeutic target for several oxidative-related diseases.

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Comparative effects of chromium, vanadium and gymnema sylvestre on sugar-induced blood pressure elevations in SHR.

Blair Anderson, S Jarrell, R Scheckenbach … (1998)

Effects on systolic blood pressure (SBP) of ingesting three agents reported to influence insulin metabolism, i.e., chromium polynicotinate, bis(maltolato)oxovanadium (BMOV), and the herb, Gymnema sylvestre, were assessed simultaneously in spontaneously hypertensive rats (SHR). In the first study, SHR were fed either a starch, sugar, or sugar diet containing chromium polynicotinate, bis(maltolato)oxovanadium (BMOV), or G. sylvestre. Tail SBP was estimated indirectly and various blood chemistries were measured. TBARS formation was determined in hepatic and renal tissue. In a second study, tail SBP was measured in SHR ingesting diets containing different concentrations of BMOV. Compared to starch, SHR consuming sucrose showed a significant elevation of SBP within days that was maintained for the duration of study. Addition of chromium polynicotinate to the sucrose diet at the beginning of study prevented the sucrose-induced elevation of SBP for 2 weeks, but SBP rose significantly after that. BMOV at high concentrations overcame the sucrose-induced rise in SBP and even decreased SBP below values seen in SHR eating the starch diet, but marked weight loss was noted. A second study examined different concentrations of BMOV. At 0.01% w/w concentration of BMOV, SBP was still significantly decreased, even though SHR did not lose body weight (BW) early on. SHR consuming G. sylvestre showed no change or even elevated SBP. Hepatic thiobarbituric acid reacting substances (TBARS) formation, an estimate of lipid peroxidation, was decreased by chromium polynicotinate and BMOV, and renal TBARS by chromium polynicotinate. Circulating cholesterol concentrations were decreased in the SHR consuming G. sylvestre. Chromium decreases the portion of SBP elevated by high sucrose intake as shown previously, but high levels of sucrose ingestion can eventually overcome this. BMOV overcame sucrose-induced elevation of SBP as well as some of the "genetic hypertension." Different from chromium, this decrease was not overcome by high levels of dietary sucrose. The significant lowering of cholesterol with G. sylvestre ingestion indicates some effect on metabolism, but G. sylvestre did not lower and even raised SBP.

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Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage

Cuneyt Caglayan, Yusuf Temel, Fatih Kandemir … (2018)

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Journal

Journal ID (nlm-ta): Biomolecules

Journal ID (iso-abbrev): Biomolecules

Journal ID (publisher-id): biomolecules

Title: Biomolecules

Publisher: MDPI

ISSN (Electronic): 2218-273X

Publication date (Electronic): 05 August 2019

Publication date Collection: August 2019

Volume: 9

Issue: 8

Electronic Location Identifier: 346

Affiliations

[1 ]Department of Medical Analysis, Princess Aisha Bint Al-Hussein Faculty of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma’an 71111, Jordan

[2 ]Department of Biology, Faculty of Science, Al-Hussein Bin Talal University, Ma’an 71111, Jordan

[3 ]Department of Biology, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia

[4 ]Department of Applied Medical Sciences, Community College of Unaizah, Qassim University, Buraydah 51431, Saudi Arabia

[5 ]Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 84428, Saudi Arabia

[6 ]Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef 62511, Egypt

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[* ]Correspondence: ayman.mahmoud@ 123456science.bsu.edu.eg

Author information

Mohammad H. Abukhalil https://orcid.org/0000-0002-4018-6925

Sultan A. M. Saghir https://orcid.org/0000-0001-7134-3199

Hamza Hanieh https://orcid.org/0000-0001-9230-3858

May Bin-Jumah https://orcid.org/0000-0002-3017-9924

Ayman M. Mahmoud https://orcid.org/0000-0003-0279-6500

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Publisher ID: biomolecules-09-00346

DOI: 10.3390/biom9080346

PMC ID: 6723184

PubMed ID: 31387329

SO-VID: 790e4725-95ac-4568-a58a-54f40cbce92c

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Galangin Activates Nrf2 Signaling and Attenuates Oxidative Damage, Inflammation, and Apoptosis in a Rat Model of Cyclophosphamide-Induced Hepatotoxicity

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Animal models of intrauterine growth restriction (IUGR)

Most cited references 45

PPARγ and Oxidative Stress: Con(β) Catenating NRF2 and FOXO

Comparative effects of chromium, vanadium and gymnema sylvestre on sugar-induced blood pressure elevations in SHR.

Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage

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