Quercetin preserves redox status and stimulates mitochondrial function in metabolically-stressed HepG2 cells

Abstract

ReuseThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) licence. This licence only allows you to download this work and share it with others as long as you credit the authors, but you can't change the article in any way or use it commercially. More information and the full terms of the licence here: https://creativecommons.org/licenses/ TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. AbstractHyperglycemia augments formation of intracellular reactive oxygen species (ROS) with associated mitochondrial damage and increased risk of insulin resistance in type 2 diabetes. We examined whether quercetin could reverse chronic high glucose-induced oxidative stress and mitochondrial dysfunction. Following long-term high glucose treatment, complex I activity was significantly decreased in isolated mitochondria from HepG2 cells. Quercetin dose-dependently recovered complex I activity and lowered cellular ROS generation under both high and normal glucose conditions. Respirometry studies showed that quercetin could counteract the detrimental increase in inner mitochondrial membrane proton leakage resulting from high glucose while it increased oxidative respiration, despite a decrease in electron transfer system (ETS) capacity, and lower non-ETS oxygen consumption. A quercetin-stimulated increase in cellular NAD + /NADH was evident within 2 h and a two-fold increase in PGC-1 mRNA within 6 h, in both normal and high glucose conditions. A similar pattern was also found for the mRNA expression of the repulsive guidance molecule b (RGMB) and its long non-coding RNA (lncRNA) RGMB-AS1 with quercetin, indicating a potential change of the glycolytic phenotype and suppression of aberrant cellular growth which is characteristic of the HepG2 cells. Direct effects of quercetin on PGC-1 activity were minimal, as quercetin only weakly enhanced PGC-1 binding to PPAR in vitro at higher concentrations. Our results suggest that quercetin may protect mitochondrial function from high glucose-induced stress by increasing cellular NAD + /NADH and activation of PGC-1 -mediated pathways. Lower ROS in combination with improved complex I activity and ETS coupling efficiency under conditions of amplified oxidative stress could reinforce mitochondrial integrity and improve redox status, beneficial in certain metabolic diseases. Abbreviations oxygen species; ROXresidual oxygen consumption; SIRTsirtuin; TBP -TATA-box binding protein; TFAMmitochondrial transcription factor A; TR-FRETtime-resolved fluorescence energy transfer.Graphical Abstract:

Antitumor Effects of Quercetin in Hepatocarcinoma In Vitro and In Vivo Models: A Systematic Review

“…After administration of quercetin, changes in tumor cell morphology in HepG2, HuH7, PLC/PRF-5, Hep3B and LM3 lines [22,25,30,31] as well as suppression of glycolytic metabolism in SMMC-7721 and BEL-7402 HCC cell lines [23] were associated with antitumor properties in HCC. This ability to reverse glycolytic metabolism of liver cancer cells is often related to the efficacy of antitumor drugs such as quercetin [61]. Furthermore, it has been described that quercetin-derived inhibition of liver cancer cell growth could be mediated by the disruption of different pathways, including protein kinase B (Akt)/mammalian target of rapamycin (mTOR) [23,24], mitogen-activated protein kinase kinase 1 (MEK1)/extracellular signal-regulated kinase 1/2 (ERK1/2) [27,38] and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling routes [22].…”

Remedying the Mitochondria to Cure Human Diseases by Natural Products

“…Polysaccharides from Portulaca oleracea L. [70] Korean red ginseng [71] Berberine [72] Quercetin [73] Theaflavins [74] Puerarin [76] Mitochondrial membrane potential imbalance Polysaccharides from Portulaca oleracea L. [70] Silibinin [75]…”

“…Silibinin [75] Mitochondrial fusion, division, and autophagy Korean red ginseng [71] Quercetin [73] Theaflavins [74] Silibinin [75] Puerarin [76] Diabetes complications…”

An Overview of the Mechanism of Penthorum chinense Pursh on Alcoholic Fatty Liver

“…Quercetin inhibited lipopolysaccharide-induced inflammation via the p38MAPK and JNK signaling pathways [ 45 ] to inhibit inflammatory mediators (release of PGE2, iNOS, COX-2, TNF- α , IL-1 β , IL-6, and NO) [ 74 ]; STAT3 proinflammatory factors play an important role in alcohol liver, and quercetin phosphorylates transcripts by inhibiting signal transducers and activating STAT3, a known PI3K inhibitor, which is also mediated by the TLR4 signaling pathway, thereby disrupting the linkage of the p85 subunit to the adapter protein MyD88 and the TLR4 complex, inhibiting downstream nuclear phosphorylation levels of transcription factor (NF- κ B) [ 48 ] and protein kinase B (a protein kinase) to treat alcohol-induced liver injury in rats [ 75 ]. Quercetin also upregulated the expression of the anti-inflammatory factor IL-10 [ 43 ], then inhibiting NLRP3 inflammasome activation and inflammatory factor secretion to maintain liver function in acute alcohol [ 46 ].…”