Hepatoprotective effect of taxifolin on cyclophosphamide-induced oxidative stress, inflammation, and apoptosis in mice: Involvement of Nrf2/HO-1 signaling

Osama Y. Althunibat; Mohammad H. Abukhalil; Muthana M.  Jghef; Manal A. Alfwuaires; Abdulmohsen I. Algefare; Bader  Alsuwayt; Reem  Alazragi; Mohammed A. S. Abourehab; Afaf F. Almuqati; Shaik  Karimulla; Saleem H. Aladaileh

doi:10.17305/bb.2022.8743

Authors

Osama Y. Althunibat Department of Medical Analysis, Princess Aisha Bint Al-Hussein College of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma’an, Jordan https://orcid.org/0000-0002-3406-9634
Mohammad H. Abukhalil Department of Medical Analysis, Princess Aisha Bint Al-Hussein College of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma’an, Jordan; Department of Biology, College of Science, Al-Hussein Bin Talal University, Ma’an, Jordan https://orcid.org/0000-0002-4018-6925
Muthana M. Jghef Department of Radiology, College of Medical Technology, Al-Kitab University, Kirkuk, Iraq https://orcid.org/0000-0001-7956-3209
Manal A. Alfwuaires Department of Biological Sciences, Faculty of Science, King Faisal University, Al-Ahsa, Saudi Arabia
Abdulmohsen I. Algefare Department of Biological Sciences, Faculty of Science, King Faisal University, Al-Ahsa, Saudi Arabia https://orcid.org/0000-0003-4603-0208
Bader Alsuwayt Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin, Saudi Arabia https://orcid.org/0000-0002-3435-7994
Reem Alazragi Department of Biochemistry, College of Science, University of Jeddah, Jeddah, Saudi Arabia https://orcid.org/0000-0003-1472-8337
Mohammed A. S. Abourehab Department of Pharmaceutics, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia https://orcid.org/0000-0003-1348-6567
Afaf F. Almuqati Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin, Saudi Arabia https://orcid.org/0000-0002-4361-6791
Shaik Karimulla Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin, Saudi Arabia https://orcid.org/0000-0001-5558-1680
Saleem H. Aladaileh Department of Medical Analysis, Princess Aisha Bint Al-Hussein College of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma’an, Jordan; Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin, Saudi Arabia https://orcid.org/0000-0003-2628-6257

DOI:

https://doi.org/10.17305/bb.2022.8743

Keywords:

Flavonoids, cyclophosphamide, inflammation, taxifolin, hepatotoxicity, oxidative damage, nuclear factor erythroid 2-related factor 2 (Nrf2)

Abstract

Taxifolin (TA) is a natural flavonoid found in many foods and medicinal plants with well-documented antioxidant and anti-inflammatory properties. Cyclophosphamide (CP) is an effective antineoplastic and immunosuppressive agent; however, it is associated with numerous adverse events, including hepatotoxicity. Herein, we aimed to investigate the potential protective effects of TA using a mouse model of CP-induced hepatotoxicity. Mice were co-treated with TA (25 and 50 mg/kg, orally) and CP (30 mg/kg, i.p.) for 10 consecutive days and sacrificed 24 hours later. CP induced increased transaminases (ALT and AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) paralleled with pronounced histopathological alterations in the liver. Moreover, hepatic tissues of CP-injected mice showed increased malondialdehyde (MDA), protein carbonyl, and nitric oxide (NO) levels, accompanied by decreased antioxidant defenses (glutathione [GSH], superoxide dismutase [SOD], and catalase [CAT]). Livers of CP-injected mice also showed increased inflammatory response (nuclear transcription factor kappa-B [NF-κB] p65 activation, increased levels of proinflammatory cytokines tumor necrosis factor alpha [TNF-α], interleukin 1 beta [IL-1β], and IL-6) and apoptosis (decreased Bcl-2 and increased Bax and caspase-3 expression levels). Remarkably, TA ameliorated markers of liver injury and histological damage in CP-injected mice. TA treatment also attenuated numerous markers of oxidative stress, inflammation, and apoptosis in the liver of CP-injected mice. This was accompanied by increased nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) expression in the liver tissues of CP-injected mice. Taken together, this study indicates that TA may represent a promising new avenue to prevent/treat CP-induced hepatotoxicity and perhaps other liver diseases associated with oxidative stress and inflammation.