Hyperpigmentation disorders causing emotional distress require the topical use of depigmenting agents of natural origin. In this study, the anti-melanogenic effects of the Lilium lancifolium root extract (LRE) were investigated in B16F10 cells. Consequently, a non-cytotoxic concentration of the extract reduced intracellular melanin content and tyrosinase activity in a dose-dependent manner, correlating with the diminished expression of core melanogenic enzymes within cells. LRE treatment also inhibited cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)/microphthalmia-associated transcription factor signaling, which regulates the expression of tyrosinase-related genes. Upon examining these findings from a molecular mechanism perspective, LRE treatment suppressed the phosphorylation of protein kinase A (PKA), p38, and extracellular signal-related kinase (ERK), which are upstream regulators of CREB. In addition, L-phenylalanine and regaloside A, specifically identified within the LRE using liquid chromatography-mass spectrometry, exhibited inhibitory effects on melanin production. Collectively, these results imply that LRE potentially suppresses cAMP-mediated melanogenesis by downregulating PKA/CREB and mitogen-activated protein kinase (MAPK)/CREB signaling pathways. Therefore, it can be employed as a novel therapeutic ingredient of natural origin to ameliorate hyperpigmentation disorders.

Polydeoxyribonucleotides (PDRN), highly purified DNA-derived polymers, were approved by the Italian Medicines Agency (AIFA) in 1994 to treat superficial wounds, skin ulcers, and dystrophic connective tissue disorders. Since then, PDRN have gained considerable attention as regenerative biomaterials. Beyond their established role in wound healing, they have also been approved as dermal fillers in several countries, with growing clinical evidence supporting their benefits for facial skin health. Recent clinical and preclinical studies suggest that PDRN may improve various skin conditions, including wrinkles, dryness, hyperpigmentation, hair loss, and barrier dysfunction. These findings have generated interest in their broader dermatological applications beyond traditional indications. This review aims to explore the therapeutic potential of PDRN for the treatment of skin disorders. We examine the efficacy and safety of PDRN-based drugs and medical devices in dermatology, with a focus on their clinical applications, pharmacological effects, and underlying molecular mechanisms. Given that PDRN consists of over 90% purified DNA, we further examine the biological functions of extracellular DNA (exDNA) and propose potential mechanisms by which PDRN may function as exDNA, beyond its classical action via the A2A receptor pathway. Collectively, current evidence highlights PDRN as safe and effective biopolymers with promising potential as DNA-based therapeutics in dermatology.

Oxidative stress and cellular senescence in dermal papilla cells (DPCs) are major etiological factors causing hair loss. In this study, the effect of the Allium hookeri extract (AHE) on hair-inductive and anti-oxidative properties was investigated in human DPCs. As a result, it was found that a non-cytotoxic concentration of the extracts increased the viability and size of the human DPC spheroid, which was associated with the increased expression of hair-growth-related genes in cells. To determine whether or not these effects could be attributed to intracellular anti-oxidative effects, liquid chromatography-mass spectrometry alongside various biochemical analyses are conducted herein. An ingredient called alliin was identified as one of the main components. Furthermore, AHE treatment induced a significant decrease in H₂O₂-mediated cytotoxicities, cell death, and cellular senescence in human DPCs. Upon analyzing these results with a molecular mechanism approach, it was shown that AHE treatment increased β-Catenin and NRF2 translocation into the nucleus while inhibiting the translocation of NF-κB (p50) through p38 and PKA-mediated phosphorylations of GSK3β, an upstream regulator of those proteins. These results overall indicate the possibility that AHE can regulate GSK3β-mediated β-Catenin, NRF2, and NF-κB signaling to enhance hair-inductive properties and ultimately protect against oxidative stress-induced cellular damage in human DPCs.

Background/Objectives: With the rapid aging of the global population, the interest in therapies for age-related diseases has increased substantially. The skin is particularly important, as aging-related changes are visible and negatively impact quality of life. Therefore, the identification of senotherapeutic candidates that are effective against skin aging is of considerable importance. Given the cost and reproducibility limitations of existing senescence models, this study established three dermal fibroblast senescence models induced by etoposide, hydrogen peroxide, and ultraviolet A, representing intrinsic and extrinsic aging. Furthermore, considering the adverse effects of current photoaging treatments, such as tretinoin and methoxsalen, we investigated the senotherapeutic potential of araliadiol, a plant-derived compound, in these models. Methods: Senescence induction and validation were assessed using trypan blue-based cell counting, senescence-associated β-galactosidase (SA-β-gal) staining, and adenosine triphosphate content assays. The senotherapeutic potential of araliadiol was further evaluated using quantitative reverse transcriptase–polymerase chain reaction, Western blotting, immunofluorescence staining, and enzyme-linked immunosorbent assay. Results: Compared with non-senescent fibroblasts, senescent cells exhibited increased SA-β-gal positivity, elevated intracellular reactive oxygen species levels, and upregulated p16 and p21 expression. The senolytic agent ABT-737 selectively induced apoptosis in senescent fibroblasts but not in non-senescent fibroblasts, validating the models. Araliadiol showed no senolytic activity but demonstrated potential senomorphic effects, including reduced expression of senescence-associated secretory phenotype (SASP) genes (IL1β, IL6, IL8, CCL2, and CXCL1) and NF-κB p65 phosphorylation, suppression of MMP-1 (up to 2.35-fold reduction) and MMP-3 (up to 30.53-fold reduction) expression and AP-1 activation, and increased extracellular procollagen type I content (up to 18.35% increase). Conclusions: Araliadiol exerted senomorphic—but not senolytic—effects across three validated dermal fibroblast senescence models, supporting its potential as a natural topical therapeutic agent for mitigating skin aging.

Background/Objectives: Inflammatory disorders contribute to the pathogenesis of numerous diseases and are known to markedly reduce quality of life. Although anti-inflammatory drugs approved by the Food and Drug Administration are available, their prolonged use is frequently associated with adverse effects. In this study, we evaluated the pharmacological properties of araliadiol, a naturally occurring polyacetylene compound, as a novel anti-inflammatory agent. Methods: An in vitro hyperinflammatory model was established by stimulating RAW 264.7 cells with lipopolysaccharide (LPS). Dexamethasone (DEX) was used as a positive control to compare anti-inflammatory efficacy. The protective effects of araliadiol against LPS-induced cytotoxicity were assessed using adenosine triphosphate content and crystal violet staining assays. The anti-inflammatory activity was further examined by quantitative reverse transcriptase–polymerase chain reaction, Western blotting, cell fractionation, immunofluorescence staining, a nitric oxide assay, and an enzyme-linked immunosorbent assay. Results: Araliadiol significantly attenuated cytotoxicity and cell death in LPS-stimulated RAW 264.7 cells. It suppressed the expression of cell death markers Cleaved caspase-3 and Cleaved PARP-1. In addition, araliadiol downregulated key pro-inflammatory mediators, including inflammasome-related genes, cytokines, chemokines, and inducible nitric oxide synthase. It also reduced the expression of Cox-2 and PGE₂, indicating potential anti-hyperalgesic effects. Moreover, araliadiol inhibited the activation of Nfκb and Stat1 signaling pathways in LPS-stimulated macrophages. Conclusions: Araliadiol demonstrated robust anti-cytotoxic, anti-inflammatory, and anti-hyperalgesic activities in LPS-induced RAW 264.7 cells, with efficacy comparable to DEX. These findings support its potential as a plant-derived therapeutic candidate for the management of inflammatory conditions.

Background: As consumer demand for cosmetic products that enhance physical appearance continues to rise, the global oxidative hair dye market is experiencing steady growth. Para-phenylenediamine (PPD), a key ingredient in most oxidative hair dyes, is widely used due to its efficacy and low cost. However, its high chemical reactivity has been consistently linked to adverse effects, including allergic contact dermatitis (ACD), eczema, carcinogenicity, and genotoxicity. Objectives: Given the concerns over the long-term use of conventional therapies such as topical corticosteroids (TCS) and calcineurin inhibitors, this study aimed to identify a plant-derived compound with protective properties in a keratinocyte model of PPD-induced toxicity. Methods: To assess the cytoprotective potential of 14 selected plant metabolites, water-soluble tetrazolium salt-1 (WST-1) and lactate dehydrogenase (LDH) assays were performed. Western blotting and reverse transcription-polymerase chain reaction were used to evaluate the anti-apoptotic, anti-DNA damage, and anti-inflammatory effects of geranyl acetate (GA), the most promising candidate. Results: Among the 14 tested plant metabolites, GA was identified as the most effective compound in mitigating cytotoxicity in HaCaT keratinocytes. Co-treatment with GA significantly attenuated PPD-induced phosphorylation of p53 and MAPK, indicating inhibition of the DNA damage response (DDR) pathway. Further experiments revealed that GA suppressed the upregulation of apoptosis-related proteins [p53 upregulated modulator of apoptosis (PUMA), B-cell lymphoma 2 (BCL-2)-associated X protein (BAX), cytochrome c, and cleaved poly (ADP-ribose) polymerase (PARP)]. Moreover, GA treatment decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and NF-κB p65, thereby downregulating five pro-inflammatory cytokines [interleukin (IL)-1α, IL-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-24] and five chemokines [C-C motif chemokine ligand (CCL) 5/RANTES, CCL20/MIP-3α, CCL26/eotaxin-3, C-X-C motif chemokine ligand (CXCL) 1/GRO-α, and CXCL8/IL-8], confirming its anti-inflammatory efficacy. Conclusions: Collectively, this study suggests GA as a promising plant-derived metabolite with cytoprotective, genoprotective, anti-apoptotic, and anti-inflammatory effects in PPD-stimulated HaCaT cells.