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The critical roles of keratinocytes and resident mast cells in skin allergy and inflammation have been highlighted in many studies. Cyclic adenosine monophosphate (cAMP), the intracellular second messenger, has also recently emerged as a target molecule in the immune reaction underlying inflammatory skin conditions. Here, we investigated whether undecane, a naturally occurring plant compound, has anti-allergic and anti-inflammatory activities on sensitized rat basophilic leukemia (RBL-2H3) mast cells and HaCaT keratinocytes and we further explored the potential involvement of the cAMP as a molecular target for undecane. We confirmed that undecane increased intracellular cAMP levels in mast cells and keratinocytes. In sensitized mast cells, undecane inhibited degranulation and the secretion of histamine and tumor necrosis factor α (TNF-α). In addition, in sensitized keratinocytes, undecane reversed the increased levels of p38 phosphorylation, nuclear factor kappaB (NF-κB) transcriptional activity and target cytokine/chemokine genes, including thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and interleukin-8 (IL-8). These results suggest that undecane may be useful for the prevention or treatment of skin inflammatory disorders, such as atopic dermatitis, and other allergic diseases.

The authors would like to modify the Conflicts of Interest Section of the following published paper [...].The authors would like to modify the Conflicts of Interest Section of the following published paper [...].

Melanin, which determines the color of the skin and hair, is initially synthesized to protect the skin from ultraviolet light; however, excessive melanin pigmentation caused by abnormal cell proliferation can result in various melanocytic lesions. Cyclic adenosine monophosphate (cAMP) is known to regulate cell cycle progression and consequently to inhibit the division of abnormally proliferating cells. In this work, we aimed to test whether carvone, a scent compound from plants, inhibits proliferation and subsequently reduces melanin content of melanoma cells and to determine whether its beneficial effects are mediated by the cAMP pathway. We found that carvone decreases melanin content and inhibits melanoma cell proliferation in a concentration-dependent manner. Meanwhile, it inhibited the activation of cell cycle-associated proteins such as cyclin-dependent kinase 1 (CDK1). Of note, the beneficial effects of carvone were abrogated by cAMP inhibition. Our findings indicate potential benefits of carvone for the treatment of melanomas and presumably other hyperpigmentation-related dermatological disorders such as melasmas, lentigines, and excessive freckles.

Chronic stress and continually high glucocorticoid levels can induce muscle atrophy. Unfortunately, there is a lack of appropriate animal models for stress-induced muscle atrophy research. Corticotropin releasing factor-overexpressing (CRF-OE) mice are a transgenic model of chronic stress that exhibit increased plasma corticosterone levels and Cushing's syndrome; however, the skeletal muscle pathology of the CRF-OE mouse has not been well studied. We observed that male, 19-week-old CRF-OE mice had significantly lower skeletal muscle mass, average cross-sectional myofiber area, and total muscle protein content than their wild type (WT) littermates. Muscle function determined by grip strength, wire-hang, and open field tests showed that 19-week-old male CRF-OE mice had impaired physical ability. Additionally, the skeletal muscles of CRF-mice exhibited decreased expression of factors involved in the IGF-1/AKT/mTOR protein synthesis pathway and increased ubiquitin proteasome pathway activity compared to the WT control mice. In conclusion, 19-week-old CRF-OE mice display numerous features of muscle atrophy and thus serve as a model for investigating stress-induced muscle atrophy and interventions to target the deleterious effects of stress on skeletal muscle.

Ultraviolet (UV) light-induced wrinkle formation is a major dermatological problem and is associated with alteration in collagen. Here, we investigated the potential of α-ionone, a naturally occurring aromatic compound, in regulation of UVB-induced photoaging in human Hs68 dermal fibroblasts and identified the mechanisms involved. We found that in human dermal fibroblasts, α-ionone inhibited UVB-induced loss of collagen. α-Ionone upregulated the molecules participating in the TGF-β–SMAD pathway (TGF-β1, phospho-SMAD2/3, Col1A1, and Col1A2), but downregulated the molecules involved in the MAPK–AP-1 signaling pathway (phospho-p38, phospho-JNK, phospho-ERK, phospho-c-Fos, phospho-c-Jun, MMP1, MMP3, and MMP9), in human dermal fibroblasts. α-Ionone treatment also increased hyaluronic acid contents, and this effect was accompanied by an upregulation of mRNA expression of genes (HAS1 and HAS2) involved in hyaluronic acid synthesis. Thus, α-ionone is effective in the prevention of UVB-induced decrease of collagen and hyaluronic acid in human dermal fibroblasts. We propose that α-ionone may prove beneficial for the prevention of UV-induced wrinkle formation and skin damage.

In recent years, there has been a great deal of interest in the ectopic roles of olfactory receptors (ORs) throughout the human body. Especially, the ectopic function of OR in the skin is one of the most actively researched areas. Suberic acid, a scent compound, was hypothesized to increase collagen synthesis in the ultraviolet B (UVB)-irradiated human dermal fibroblasts (Hs68) through a specific olfactory receptor. Suberic acid ameliorated UVB-induced decreases in collagen production in Hs68 cells. Using in silico docking to predict the binding conformation and affinity of suberic acid to 15 ectopic ORs detectable in Hs68, several ORs were identified as promising candidates. The effect of suberic acid on collagen synthesis in UVB-exposed dermal fibroblasts was nullified only by a reduction in OR10A3 expression via specific siRNA. In addition, using the cells transiently expressing OR10A3, we demonstrated that suberic acid can activate OR10A3 by assessing the downstream effector cAMP response element (CRE) luciferase activity. We examined that the activation of OR10A3 by suberic acid subsequently stimulates collagen synthesis via the downstream cAMP-Akt pathway. The findings support OR10A3 as a promising target for anti-aging treatments of the skin.

The authors would like to modify the Conflicts of Interest section of the published paper [...]

Over several decades, excess glucocorticoids (GCs) of endogenous or exogenous origin have been recognized to significantly inhibit collagen synthesis and accelerate skin aging. However, little is known regarding their molecular mechanisms. We hypothesized that the action of GCs on collagen production is at least partially through the glucocorticoid receptor (GR) and its target genes, and therefore aimed to identify GR target genes that potentially inhibit collagen synthesis in Hs68 human dermal fibroblasts. We first confirmed that dexamethasone, a synthetic GC, induced canonical GR signaling in dermal fibroblasts. We then collected 108 candidates for GR target genes reported in previous studies on GR target genes and verified that 17 genes were transcriptionally upregulated in dexamethasone-treated dermal fibroblasts. Subsequently, by individual knockdown of the 17 genes, we identified that six genes, AT-rich interaction domain 5B, FK506 binding protein 5, lysyl oxidase, methylenetetrahydrofolate dehydrogenase (NADP + dependent) 2, zinc finger protein 36, and zinc fingers and homeoboxes 3, are potentially involved in GC-mediated inhibition of collagen synthesis. The present study sheds light on the molecular mechanisms of GC-mediated skin aging and provides a basis for further research on the biological characteristics of individual GR target genes.

The authors wish to make the following change to their paper [...]

Stress is a major contributing factor of skin aging, which is clinically characterized by wrinkles, loss of elasticity, and dryness. In particular, glucocorticoids are generally considered key hormones for promoting stress-induced skin aging through binding to glucocorticoid receptors (GRs). In this work, we aimed to investigate whether β-ionone (a compound occurring in various foods such as carrots and almonds) attenuates dexamethasone-induced suppression of collagen and hyaluronic acid synthesis in human dermal fibroblasts, and to explore the mechanisms involved. We found that β-ionone promoted collagen production dose-dependently and increased mRNA expression levels, including collagen type I α 1 chain (COL1A1) and COL1A2 in dexamethasone-treated human dermal fibroblasts. It also raised hyaluronic acid synthase mRNA expression and hyaluronic acid levels. Notably, β-ionone inhibited cortisol binding to GR, subsequent dexamethasone-induced GR signaling, and the expression of several GR target genes. Our results reveal the strong potential of β-ionone for preventing stress-induced skin aging and suggest that its effects are related to the inhibition of GR signaling in human dermal fibroblasts.