Differential roles of 3-Hydroxyflavone and 7-Hydroxyflavone against nicotine-induced oxidative stress in rat renal proximal tubule cells

Abstract

Plant flavonoids are well known as antioxidants against oxidative stress induced by exposure to external pollutants. Nicotine (NIC) is one of those agents which increases renal oxidative stress, an important factor in the pathogenesis of renal epithelial injury in smokers. Although several studies had been conducted on flavonoids and oxidative stress, the mechanism of the protective pathways are not fully understood. Here, we present studies on antioxidant properties of two mono-hydroxyflavone isomers, 3-hydroxyflanove (3HF)- and 7-hydroxyflavone (7HF), against nicotine-associated oxidative stress and injury in cultured renal proximal tubule cells and correlate their antioxidant properties with their chemical structure. Our data clearly demonstrates, for the first time, that while both 3HF and 7HF protect renal cells from NIC-associated cytotoxicity, the mechanism of their action is different: 3HF elicits protective activity via the PKA/CREB/MnSOD pathway while 7HF does so via the ERK/Nrf2/HO-1 pathway. Molecular docking and dynamics simulations with two major signaling pathway proteins showed significant differences in the binding energies of 3HF (-5.67 and -7.39 kcal.mol-1) compared to 7HF (-5.41 and -8.55 kcal.mol-1) in the matrices of CREB and Keap1-Nrf2 proteins respectively, which corroborate with the observed differences in their protective properties in the renal cells. The implications of this novel explorative study is likely to promote the understanding of the mechanisms of the antioxidative functions of different flavones.

Flavonoids in Kidney Health and Disease

“…The general and common mechanism of action of flavonoids is their attenuation of renal oxidative stress and inflammation. Flavonoids that have been reported to protect rat or mouse kidney against nephrotoxic agents include: flavocoxid (El-Kashef et al, 2015 ), pinocembrin (Promsan et al, 2016 ), and gossypin (Katary and Salahuddin, 2017 ), which attenuated gentamicin-induced nephrotoxicity in rats; trigonella foenum-graecum (TFG) seeds (Pribac et al, 2015 ), which prevented cell deterioration and improved renal morphology and function in the kidney of alcoholized rats; hydroxyflavone and 7-hydroxyflavone, which protected against nicotine-induced oxidative stress (Sengupta et al, 2017 ); baicalin, which protected against lead-induced renal oxidative damage in mice (Zhang et al, 2017 ); and epigallocatechin-3-gallate, which attenuated cadmium-induced chronic renal injury/fibrosis (Chen et al, 2016 ) and reduced contrast-induced renal injury alone (Gao et al, 2016 ) or with glycerol-induced renal damage (Palabiyik et al, 2017 ).…”

Transepithelial Anti-Neuroblastoma Response to Kale among Four Vegetable Juices Using In Vitro Model Co-Culture System

“…Moreover, lettuce and dandelion juices showed a shoulder emission peak at 560 nm, which is even more prominent in lettuce when λ ex = 350 nm (having the main emission at ~450 nm for lettuce and kale and the main at ~460 nm for dandelion). It is pertinent to mention that absorption spectroscopy pertains to the ground state characteristics ( Figure 7 A) whereas fluorescence excitation spectra looks at the excited states of the fluorophores ( Figure 7 B) [ 70 ], which is responsible for the difference in and respectively.…”

“…A second emission band at 560 nm in Figure 7 D (mainly for lettuce) suggests this juice could contain cis-piceid along with other polyphenolic compounds as was reported by Poutaraud, A. et al [ 99 ]. The absorption (λ abs ~330 nm) and fluorescence spectral profiles (λ ex/em ~350/460 nm) of the vegetable juices also bear close resemblance with isoflavones [ 70 ] and flavanols [ 100 ]. Plus, the absence of a signal -N=C=S at ~1322 cm −1 band in the FTIR spectra ( Figure 8 A,B) of kale and dandelion, compared to lettuce and spinach, suggests that the isothiocyanates (SFNs) in kale and dandelion exist in forms other than as phenyl, methyl, tert-butyl, and ∝-naphthyl isothiocyanate [ 72 ].…”

Mechanism of Action of Flavonoids of Oxytropis falcata on the Alleviation of Myocardial Ischemia–Reperfusion Injury

“…In addition, naringenin protects against MIRI by regulating the NRF2/System xc-/GPX4 axis and cGMP-PKGIα signaling pathway [ 69 , 70 ]. Other compounds of O. falcata such as 7-hydroxyflavone and isoliquiritigenin also exert anti-inflammatory and antioxidant effects and can attenuate diabetic cardiomyopathy [ 71 , 72 , 73 ]. The putative targets in MIRI were also identified by PPI network analysis and included TNF, AKT1, VEGFA, SRC, EGFR, JUN, and PTGS2 as the core genes.…”