MLK3 is a novel target of dehydroglyasperin D for the reduction in UVB‐induced COX‐2 expression in vitro and in vivo

Abstract

Dehydroglyasperin D (DHGA-D), a compound present in licorice, has been found to exhibit anti-obesity, antioxidant and anti-aldose reductase effects. However, the direct molecular mechanism and molecular targets of DHGA-D during skin inflammation remain unknown. In the present study, we investigated the effect of DHGA-D on inflammation and its mechanism of action on UVB-induced skin inflammation in HaCaT human keratinocytes and SKH-1 hairless mice. DHGA-D treatment strongly suppressed UVB-induced COX-2 expression, PGE2 generation and AP-1 transactivity in HaCaT cells without affecting cell viability. DHGA-D also inhibited phosphorylation of the mitogen-activated protein kinase kinase (MKK) 3/6/p38, MAPK/Elk-1, MKK4/c-Jun N-terminal kinase (JNK) 1/2/c-Jun/mitogen, and stress-activated protein kinase (MSK), whereas phosphorylation of the mixed-lineage kinase (MLK) 3 remained unaffected. Kinase and co-precipitation assays with DHGA-D Sepharose 4B beads showed that DHGA-D significantly suppressed MLK3 activity through direct binding to MLK3. Knockdown of MLK3 suppressed COX-2 expression as well as phosphorylation of MKK4/p38 and MKK3/6/JNK1/2 in HaCaT cells. Furthermore, Western blot assay and immunohistochemistry results showed that DHGA-D pre-treatment significantly inhibits UVB-induced COX-2 expression in vivo. Taken together, these results indicate that DHGA-D may be a promising anti-inflammatory agent that mediates suppression of both COX-2 expression and the MLK3 signalling pathway through direct binding and inhibition of MLK3.

Alleviation of Ultraviolet B-Induced Photodamage by Coffea arabica Extract in Human Skin Fibroblasts and Hairless Mouse Skin

“…Studies have demonstrated that the levels and expressions of proinflammatory factors, such as COX-2 and ILs, are induced by UVB exposure [ 7 , 9 ]. In the current study, CAE reduced UVB-induced COX-2 expression in fibroblasts and the hairless mouse skin, preventing the skin from photodamage.…”

“…UV irradiation produces peroxynitrite and ROS [ 6 ]. ROS upregulate cyclooxygenase (COX)-2 expression to stimulate inflammation, which then cause skin erythema and sunburn [ 7 , 8 , 9 ]. UV exposure generates prostaglandin E2 and leukotrienes that lead to erythema, edema, and inflammation [ 10 ].…”

Dehydroglyasperin D Inhibits the Proliferation of HT-29 Human Colorectal Cancer Cells Through Direct Interaction With Phosphatidylinositol 3-kinase

“… 9 , 10 , 13 , 20 In our recent study, DHGA-D exhibited chemopreventive properties with anti-inflammatory effects and directly suppressed mixed-lineage kinase activity. 21 However, its biological functions and underlying molecular mechanisms in colon cancer have not been previously investigated.…”

Preventive Effect of Pharmaceutical Phytochemicals Targeting the Src Family of Protein Tyrosine Kinases and Aryl Hydrocarbon Receptor on Environmental Stress-Induced Skin Disease

“…As with other inflammation, it is accompanied by redness, swelling, and pain, and these are representative symptoms of erythema. In previous in vivo studies, acute UVB exposure (0.5 J/cm 2 ) resulted in skin inflammation and increased thickness of the epidermis in ICR and SKH-1 hairless mice [ 16 , 31 ].…”