Reactive oxygen species (ROS) play a major role in both chronological aging and photoaging. ROS induce skin aging through their damaging effect on cellular constituents. However, the origins of ROS have not been fully elucidated. We investigated that ROS generation of replicative senescent fibroblasts is generated by the modulation of phosphatidylinositol 3,4,5‐triphosphate (PIP3) metabolism. Reduction of the PTEN protein, which dephosphorylates PIP3, was responsible for maintaining a high level of PIP3 in replicative cells and consequently mediated the activation of the phosphatidylinositol‐3‐OH kinase (PI3K)/Akt pathway. Increased ROS production was blocked by inhibition of PI3K or protein kinase C (PKC) or by NADPH oxidase activating in replicative senescent cells. These data indicate that the signal pathway to ROS generation in replicative aged skin cells can be stimulated by reduced PTEN level. Our results provide new insights into skin aging‐associated modification of the PI3K/NADPH oxidase signaling pathway and its relationship with a skin aging‐dependent increase of ROS in human dermal fibroblasts.

Allergic rhinitis (AR), a chronic respiratory inflammatory disease, is among the most common chronic diseases reported worldwide. Mucus hypersecretion is a critical feature of AR pathogenesis. Although the Gleditsia sinensis extract has several beneficial effects on human health, its effects on allergic inflammation have not yet been investigated. In this study, we examined the effects of G. sinensis aqueous extract (GSAE) on nasal inflammation in an ovalbumin (OVA)-induced AR mouse model. GSAE was administered orally for 1 week and then the clinical nasal symptoms were evaluated. The levels of histamine, OVA-specific immunoglobulin (Ig) E, and interleukin (IL)-13 were measured in the serum using an enzyme-linked immunosorbent assay (ELISA). Inflammatory cells were then counted in the nasal lavage fluid (NALF) and histopathology in the nasal epithelium was evaluated. STAT3/STAT6 phosphorylation was examined in primary human nasal epithelial cells (HNEpCs) using western blot analysis. Oral administration of GSAE to OVA-induced AR mice alleviated nasal clinical symptoms and reduced OVA-specific immunoglobulin E, interleukin (IL)-13, and histamine levels. The accumulation of eosinophils in nasal lavage fluid, nasal mucosa, mast cells, goblet cells, and mucin 5AC (MUC5AC) in the nasal epithelium was also inhibited by GSAE. Treatment with GSAE inhibited the production of MUC5AC in IL-4/IL-13-stimulated primary human nasal epithelial cells through the signal transducer and activator of transcription (STAT)3/STAT6 signaling pathway. These results indicated that GSAE reduces nasal inflammation suggesting that it is a potential treatment option for AR.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. AD pathogenesis is associated with increased oxidative stress, impairment of the skin barrier, and activation of the immune response. Rosmarinic acid (RA), a caffeic acid ester, is known for its anti-inflammatory and antioxidant properties. However, the effects of RA on Dermatophagoides farinae extract (DfE)-induced AD-like skin inflammation, as well as its ability to regulate oxidative stress through the Nrf2/HO-1 pathway in TNF-α/IFN-γ-treated keratinocytes, remain unclear. We investigated RA activity in a DfE-induced AD-like skin inflammation mouse model and IFN-γ/TNF-α-stimulated keratinocytes. We found that RA attenuates DfE-induced inflammation by decreasing dermatitis scores and serum inflammatory marker levels and mast cell infiltration. Additionally, RA significantly suppressed IFN-γ/TNF-α-induced chemokine production in keratinocytes and reduced Th cytokine levels in concanavalin A-stimulated splenocytes. Importantly, RA also increased Nrf2/HO-1 expression in TNF-α/IFN-γ-treated keratinocytes. In conclusion, this study demonstrated that RA effectively alleviates DfE-induced AD-like skin lesions by reducing the levels of inflammatory cytokines and chemokines. Furthermore, RA promotes Nrf2/HO-1 signaling in keratinocytes, which may help mitigate DfE-induced oxidative stress, thereby alleviating AD-like skin inflammation. These findings highlight the potential of RA as a therapeutic agent for treating AD and other skin inflammation.

The constituents of Peucedanum japonicum Thunb. (PJ) exhibit biological and pharmacological activities, including anti‑obesity, anti‑oxidant and anti‑allergic activities. The aim of the present study was to examine in vitro effects of PJ in RANKL‑induced signaling pathways, which determine osteoclast differentiation. PJ ethanol extract (PEE) exhibited anti‑osteoporotic activity by disrupting the phospholipase C (PLC)‑Ca2+‑c‑Fos/cAMP response element‑binding protein (CREB)‑nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) signaling pathway during osteoclastogenesis. Murine bone marrow‑derived macrophages (BMMs) were cultured and used to determine the effects of PJ in the receptor activator of nuclear factor κB ligand (RANKL)‑mediated osteoclastogenesis. The effects of PEE in the RANKL‑mediated signaling cascade were evaluated using a standard in vitro osteoclastogenesis system. PEE treatment of BMMs significantly reduced the number of RANKL‑mediated tartrate resistant acid phosphatase (TRAP)‑positive multinucleated cells (P<0.05 for 5 and 10 µg/ml PEE, P<0.01 for 25 and 50 µg/ml PEE), without cytotoxic effects. Furthermore, the expression of differentiation‑related marker genes, including TRAP, Oscar, Cathepsin K, dendrocyte expressed seven transmembrane protein, ATPase H+ Transporting V0 Subunit D2 and NFATc1, were markedly suppressed. PEE induced a transient increase in free cytoplasmic Ca2+ ([Ca2+]i) mobilization via voltage‑gated Ca2+ channels and PLC‑sensitive pathways. Transient [Ca2+]i increase consequently resulted in the suppression of c‑Fos, CREB and NFATc1 activities. These findings highlight the potential use of PJ in treating bone disorders caused by osteoclast overgrowth.

Atopic dermatitis (AD) is a skin allergy accompanied by acute and chronic dermal inflammation. In traditional oriental medicine, Laminaria japonica has been used to treat various diseases, including inflammatory diseases. Therefore, to determine the therapeutic potential of L. japonica against AD, we investigated the inhibitory effects of L. japonica water extract (LJWE) on the inflammatory mediators and AD-like skin lesions. We determined the cell viability of LJWE-treated HaCaT cells using the cell counting kit-8 assay and the levels of inflammatory cytokines using cytometric bead array kits. Additionally, we analyzed the modulatory effects of LJWE on the signaling pathways in tumor necrosis factor-α/interferon-γ-stimulated HaCaT cells via Western blotting. Furthermore, we determined the in vivo effect of LJWE on NC/Nga mice and found that LJWE remarkably improved the skin moisture, reduced dermatitis severity, and inhibited the overproduction of inflammatory mediators in 2,4-dinitrochlorobenzene-sensitized NC/Nga mice. We also observed that LJWE inhibits the expression of inflammatory chemokines in human keratinocytes by downregulating the p38 mitogen-activated protein kinase signaling pathway and activating the signal transducer and activator of transcription 1. In conclusion, LJWE has the therapeutic potential against AD by healing AD-like skin lesions, and suppressing inflammatory mediators and major signaling molecules.

Atopic dermatitis is caused by various factors, including complex interactions between immune responses and imbalances in T helper cells. In order to resolve the side effects of steroid-based treatment and rapidly improve atopy symptoms, the development of preventive substances for new treatments and as food supplements is essential. Pulsatilla koreana Nakai (PKN) is traditionally used as an effective herbal medicine for pain relief, anti-inflammation, and edema, and dried PKN is boiled and drunk as a tea to prevent them; however, its effect on skin manifestations such as atopy are unclear. Therefore, we investigated the in vivo and in vitro effects of PKN extract on improving symptoms of atopy as a potential treatment. By evaluating dermatitis scores and conducting histopathological analysis in mice with Dermatophagoides farina-induced atopy-like pathology, we demonstrated that PKN extract alleviated atopy symptoms. Moreover, PKN extract restored a reduction in the protein levels of skin barrier-related factors in skin tissue. Through in vitro analysis, we examined the impact of PKN on JAK/STAT signaling in IL-4/IL-13-stimulated human keratinocytes and elucidated the mechanisms that suppress the levels of skin barrier factors and inflammation. PKN extract inhibited JAK/STAT phosphorylation stimulated by IL-4/IL-13. Furthermore, docking analysis of PKN constituents indicated binding to JNK1/2 and STAT3/6 and a subsequent inhibition of signal transduction. Therefore, this suggests that PKN extract has potential not only as a treatment but also as a food supplement to improve atopic dermatitis by strengthening skin barrier factors and inhibiting key signaling molecules.