Anti-Inflammatory, Antioxidant, Moisturizing, and Antimelanogenesis Effects of Quercetin 3-O-β-D-Glucuronide in Human Keratinocytes and Melanoma Cells via Activation of NF-κB and AP-1 Pathways

Int J Mol Sci. 2021 Dec 31;23(1):433. doi: 10.3390/ijms23010433.

Abstract

Quercetin 3-O-β-D-glucuronide (Q-3-G), the glucuronide conjugate of quercetin, has been reported as having anti-inflammatory properties in the lipopolysaccharide-stimulated macrophages, as well as anticancer and antioxidant properties. Unlike quercetin, which has been extensively described to possess a wide range of pharmacological activities including skin protective effects, the pharmacological benefits and mechanisms Q-3-G in the skin remained to be elucidated. This study focused on characterizing the skin protective properties, including anti-inflammatory and antioxidant properties, of Q-3-G against UVB-induced or H2O2-induced oxidative stress, the hydration effects, and antimelanogenesis activities using human keratinocytes (HaCaT) and melanoma (B16F10) cells. Q-3-G down-regulated the expression of the pro-inflammatory gene and cytokine such as cyclooxygenase-2 (COX-2) and tumor necrosis factor (TNF)-α in H2O2 or UVB-irradiated HaCaT cells. We also showed that Q-3-G exhibits an antioxidant effect using free radical scavenging assays, flow cytometry, and an increased expression of nuclear factor erythroid 2- related factor 2 (Nrf2). Q-3-G reduced melanin production in α-melanocyte-stimulating hormone (α-MSH)-induced B16F10 cells. The hydration effects and mechanisms of Q-3-G were examined by evaluating the moisturizing factor-related genes, such as transglutaminase-1 (TGM-1), filaggrin (FLG), and hyaluronic acid synthase (HAS)-1. In addition, Q-3-G increased the phosphorylation of c-Jun, Jun N-terminal kinase (JNK), Mitogen-activated protein kinase (MAPK) kinase 4 (MKK4), and TAK1, involved in the MAPKs/AP-1 pathway, and the phosphorylation of IκBα, IκB kinase (IKK)-α, Akt, and Src, involved in the NF-κB pathway. Taken together, we have demonstrated that Q-3-G exerts anti-inflammatory, antioxidant, moisturizing, and antimelanogenesis properties in human keratinocytes and melanoma cells through NF-κB and AP-1 pathways.

Keywords: AP-1; NF-κB; UV protection; antimelanogenesis; moisturizing; quercetin 3-O-β-D-glucuronide.

MeSH terms

  • Anti-Inflammatory Agents / pharmacology*
  • Antioxidants / pharmacology*
  • HEK293 Cells
  • HaCaT Cells
  • Humans
  • Hydrogen Peroxide / toxicity
  • Keratinocytes / drug effects
  • Keratinocytes / pathology*
  • Keratinocytes / radiation effects
  • Melanins / metabolism*
  • Melanoma, Experimental / pathology*
  • Models, Biological
  • NF-kappa B / metabolism*
  • Quercetin / analogs & derivatives*
  • Quercetin / chemistry
  • Quercetin / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / radiation effects
  • Transcription Factor AP-1 / metabolism*
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics
  • Transcriptional Activation / radiation effects
  • Ultraviolet Rays

Substances

  • Anti-Inflammatory Agents
  • Antioxidants
  • Melanins
  • NF-kappa B
  • Transcription Factor AP-1
  • quercetin 3-O-glucuronide
  • Quercetin
  • Hydrogen Peroxide