2. Academic Validation
  3. The Flavonoid Hesperidin Methyl Chalcone Targets Cytokines and Oxidative Stress to Reduce Diclofenac-Induced Acute Renal Injury: Contribution of the Nrf2 Redox-Sensitive Pathway

The Flavonoid Hesperidin Methyl Chalcone Targets Cytokines and Oxidative Stress to Reduce Diclofenac-Induced Acute Renal Injury: Contribution of the Nrf2 Redox-Sensitive Pathway

  • Antioxidants (Basel). 2022 Jun 27;11(7):1261. doi: 10.3390/antiox11071261.
Allan J C Bussmann 1,  Tiago H Zaninelli 1,  Telma Saraiva-Santos 1,  Victor Fattori 1,  Carla F S Guazelli 1,  Mariana M Bertozzi 1,  Ketlem C Andrade 1,  Camila R Ferraz 1,  Doumit Camilios-Neto 2,  Antônio M B Casella 3,  Rubia Casagrande 4,  Sergio M Borghi 1 5,  Waldiceu A Verri Jr 1
Affiliations

Affiliations

  • 1 Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Londrina State University, Londrina 86057-970, Brazil.
  • 2 Department of Biochemistry and Biotechnology, Center of Exact Sciences, Londrina State University, Londrina 86057-970, Brazil.
  • 3 Department of Internal Medicine, Center of Health Sciences, Londrina State University, Londrina 86039-440, Brazil.
  • 4 Department of Pharmaceutical Sciences, Center of Health Sciences, Londrina State University, Londrina 86039-440, Brazil.
  • 5 Center for Research in Health Sciences, University of Northern Paraná, Londrina 86041-140, Brazil.
PMID: 35883752 DOI: 10.3390/antiox11071261
Abstract

Hesperidin is derived from citrus fruits among other Plants. Hesperidin was methylated to increase its solubility, generating hesperidin methyl chalcone (HMC), an emerging flavonoid that possess anti-inflammatory and antioxidant properties. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a powerful regulator of cellular resistance to oxidant products. Previous data evidenced HMC can activate Nrf2 signaling, providing antioxidant protection against diverse pathological conditions. However, its effects on kidney damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) have not been evaluated so far. Mice received a nephrotoxic dose of diclofenac (200 mg/kg) orally followed by intra-peritoneal (i.p.) administration of HMC (0.03-3 mg/kg) or vehicle. Plasmatic levels of urea, creatinine, oxidative stress, and cytokines were assessed. Regarding the kidneys, oxidative parameters, cytokine production, kidney swelling, urine NGAL, histopathology, and Nrf2 mRNA expression and downstream targets were evaluated. HMC dose-dependently targeted diclofenac systemic alterations by decreasing urea and creatinine levels, and lipid peroxidation, as well as IL-6, IFN-γ, and IL-33 production, and restored antioxidant properties in plasma samples. In kidney samples, HMC re-established antioxidant defenses, inhibited lipid peroxidation and pro-inflammatory cytokines and upregulated IL-10, reduced kidney swelling, urine NGAL, and histopathological alterations. Additionally, HMC induced mRNA expression of Nrf2 and its downstream effectors HO-1 and Nqo1, as well as reduced the levels of Keap1 protein detected in renal tissue. The present data demonstrate HMC is a potential compound for the treatment of acute renal damage caused by diclofenac, a routinely prescribed non-steroidal anti-inflammatory drug.

Keywords

Nrf2; acute renal injury; citrus flavonoid; diclofenac; hesperidin methylchalcone; oxidative stress.

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