Nrf2 Activation by SK-119 Attenuates Oxidative Stress, UVB, and LPS-Induced Damage

Abstract

Background/Aims: The Nrf2 signaling pathway plays a pivotal role in neutralizing excess reactive oxygen species formation and therefore enhancing the endogenous cellular protection mechanism. Thus, activating this pathway may provide therapeutic options against oxidative stress-related disorders. We have recently applied a computer-aided drug design approach to the design and synthesis of novel Nrf2 enhancers. The current study was aimed at investigating the potential beneficial impact of (E)-5-oxo-1-(4-((2,4,6-trihydroxybenzylidene)amino)phenyl)pyrrolidine-3-carboxylic acid (SK-119) in skin oxidative damage models. Methods: SK-119, tested initially in PC-12 cells, attenuated oxidative stress-induced cytotoxicity concomitantly with Nrf2 activation. The potential impact of this compound was evaluated in skin-based disease models both in vitro (HaCaT cells) and ex vivo (human skin organ culture). Results: The data clearly showed the marked anti-inflammatory and photoprotection properties of the compound; SK-119-treated cells or tissues displayed a reduction in cytokine secretion induced by lipopolysaccharides (LPS) in a manner comparable with dexamethasone. In addition, topical application of SK-119 was able to block UVB-induced oxidative stress and attenuated caspase-mediated apoptosis, DNA adduct formation, and the concomitant cellular damage. Conclusion: These results indicate that SK-119 is an Nrf2 activator that can be used as a prototype molecule for the development of novel treatments of dermatological disorders related to oxidative stress.

Kinetic Cytokine Secretion Profile of LPS-Induced Inflammation in the Human Skin Organ Culture

“…Here we show that the efficacy and potency of three selected LPS types (E.coli O111:B4; Salmonella enterica serotype enteritidis; Salmonella enterica serotype typhimurium) in inducing cytokine secretion varies. This may also account for some of the variability of results in other studies [14,16,20,28]. Thus, in order to increase the reproducibility among researchers and get additional insights into results, the specific origin and supplier of LPS should be clearly stated.…”

“…A mechanical skin press apparatus was used to section the skin to 0.8 × 0.8 cm 2 pieces, as previously described [15]. The skin explants were maintained in an air-liquid interface, dermal side submerged in the medium, as described before [16]. Serum-free Dulbecco's Modified Eagle Medium (DMEM, 265 mg/L calcium), supplemented with 100 µg/mL penicillin and 100 µg/mL streptomycin, were used.…”

Medicinal properties of jojoba (Simmondsia chinensis)

“…In addition to its structural importance to the formulation stability, jojoba oil also serves as a carrier and enhancer of the active compounds (Nasr et al 2016). In addition, the antioxidant and tocopherol content of jojoba mentioned above may be used to reduce skin-related oxidative stress (Kahremany et al 2019). However, it should be noted that jojoba can also exert contact dermatitis (Wantke et al 1996;Di Berardino et al 2006) and may be absorbed systemically if high topical amounts are applied (Yaron et al 1980;Matsumoto et al 2019).…”

<i>Dunaliella salina</i> and <i>Haloferax volcanii</i> Synergistically Attenuate Skin Cancer <i>in Vitro</i>

“…The ability of the compounds to reduced cancer cell viability was evaluated by an MTT assay, as previously reported, with minor modifications [4]. Briefly, the cells were incubated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (0.5 mg/ml) in PBS for 1 hr at 37˚C.…”

“…The latter induces direct damage to macromolecules within the cells, including proteins, membranes, and DNA, and regards as the major risk factors for skin cancers formation [3]. UVB-induced carcinogenesis is related to UV absorption by the cell's DNA, which results in DNA breakdown, and production of mutagenic dimeric photoproducts, namely cyclobutane-pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) [4]. Both genetic and environmental factors converge eventually to an imbalance between proliferation and differentiation states of the cells and alter their ability to migrate and escape the immune system [5].…”