Phloroglucinol Enhances Anagen Signaling and Alleviates H2O2-Induced Oxidative Stress in Human Dermal Papilla Cells.

Phloroglucinol (PG) is one of the abundant isomeric benzenetriols in brown algae. Due to its polyphenolic structure, PG exhibits various biological activities. However, the impact of PG on anagen signaling and oxidative stress in human dermal papilla cells (HDPCs) is unknown. In this study, we investigated the therapeutic potential of PG for improving hair loss. A non-cytotoxic concentration of PG increased anagen-inductive genes and transcriptional activities of ß-Catenin. Since several anagen-inductive genes are regulated by ß-Catenin, further experiments were performed to elucidate the molecular mechanism by which PG upregulates anagen signaling. Various biochemical analyses revealed that PG upregulated ß-Catenin signaling without affecting the expression of Wnt. In particular, PG elevated the phosphorylation of protein kinase B (AKT), leading to an increase in the inhibitory phosphorylation of glycogen synthase kinase 3 beta (GSK3ß) at serine 9. Treatment with the selective phosphoinositide 3-kinase/AKT inhibitor, LY294002, restored the increased AKT/GSK3ß/ß-Catenin signaling and anagen-inductive proteins induced by PG. Moreover, conditioned medium from PG-treated HDPCs promoted the proliferation and migration of human epidermal keratinocytes via the AKT signaling pathway. Subsequently, we assessed the antioxidant activities of PG. PG ameliorated the elevated oxidative stress markers and improved the decreased anagen signaling in hydrogen peroxide (H2O2)-induced HDPCs. The senescence-associated ß-galactosidase staining assay also demonstrated that the antioxidant abilities of PG effectively mitigated H2O2-induced senescence. Overall, these results indicate that PG potentially enhances anagen signaling and improves oxidative stress-induced cellular damage in HDPCs. Therefore, PG can be employed as a novel therapeutic component to ameliorate hair loss symptoms.

Pan-EGFR Inhibitor Dacomitinib Resensitizes Paclitaxel and Induces Apoptosis via Elevating Intracellular ROS Levels in Ovarian Cancer SKOV3-TR Cells.

Paclitaxel is still used as a standard first-line treatment for ovarian cancer. Although paclitaxel is effective for many types of cancer, the emergence of chemoresistant cells represents a major challenge in chemotherapy. Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity. Additionally, we confirmed that dacomitinib inhibits chemoresistance in paclitaxel-resistant ovarian cancer HeyA8-MDR cells. Collectively, our research indicated that dacomitinib effectively resensitized paclitaxel in SKOV3-TR cells by inhibiting EGFR signaling and elevating intracellular ROS levels.

Skin-Whitening Effect of a Callus Extract of Nelumbo nucifera Isolate Haman.

The sacred lotus (Nelumbo nucifera Gaertn. Isolate Haman, in the family Nelumbonaceae) used in this study originated from the Haman region of Korea, and lotus seeds dating back to the Goryeo Dynasty (650-760 years ago) were accidentally discovered. Lotus is known to possess antioxidant, anti-inflammatory, and soothing properties. Instead of using the lotus alone, we obtained extracts using Haman region lotus-derived callus (HLC), which allowed for a controlled, quantitative, and infinite supply. Based on the reported effects of the lotus, we formulated a hypothesis to investigate the skin-whitening effect of the HLC extract (HLCE). The HLCE was first obtained by extraction with distilled water and using 5% propanediol as a solvent and subsequently verified for the whitening effect (melanin content tests) using mammalian cells in vitro. Its efficacy at the molecular level was confirmed through real-time polymerase chain reaction (PCR) using melanin-related genes. Furthermore, clinical trials with 21 volunteers confirmed the significant whitening effect of cosmetics containing the HLCE. In conclusion, we found that the HLCE not only has anti-inflammatory, antioxidant, and skin-soothing properties but also plays an essential role in skin whitening. Therefore, we propose that the HLCE has the potential to become a new raw material for the cosmetic industry.

Tephrosin Suppresses the Chemoresistance of Paclitaxel-Resistant Ovarian Cancer via Inhibition of FGFR1 Signaling Pathway.

Ovarian cancer is the leading cause of death among gynecologic cancers. Paclitaxel is used as a standard first-line therapeutic agent for ovarian cancer. However, chemotherapeutic resistance and high recurrence rates are major obstacles to treating ovarian cancer. We have found that tephrosin, a natural rotenoid isoflavonoid, can resensitize paclitaxel-resistant ovarian cancer cells to paclitaxel. Cell viability, immunoblotting, and a flow cytometric analysis showed that a combination treatment made up of paclitaxel and tephrosin induced apoptotic death. Tephrosin inhibited the phosphorylation of AKT, STAT3, ERK, and p38 MAPK, all of which simultaneously play important roles in survival signaling pathways. Notably, tephrosin downregulated the phosphorylation of FGFR1 and its specific adapter protein FRS2, but it had no effect on the phosphorylation of the EGFR. Immunoblotting and a fluo-3 acetoxymethyl assay showed that tephrosin did not affect the expression or function of P-glycoprotein. Additionally, treatment with N-acetylcysteine did not restore cell cytotoxicity caused by a treatment combination made up of paclitaxel and tephrosin, showing that tephrosin did not affect the reactive oxygen species scavenging pathway. Interestingly, tephrosin reduced the expression of the anti-apoptotic factor XIAP. This study demonstrates that tephrosin is a potent antitumor agent that can be used in the treatment of paclitaxel-resistant ovarian cancer via the inhibition of the FGFR1 signaling pathway.

Anti-Melanogenic Effects of Lilium lancifolium Root Extract via Downregulation of PKA/CREB and MAPK/CREB Signaling Pathways in B16F10 Cells.

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.

Identification of Loliolide with Anti-Aging Properties from Scenedesmus deserticola JD052.

Herein, different extracts of Scenedesmus deserticola JD052, a green microalga, were evaluated in vitro as a potential anti-aging bioagent. Although post-treatment of microalgal culture with either UV irradiation or high light illumination did not lead to a substantial difference in the effectiveness of microalgal extracts as a potential anti-UV agent, the results indicated the presence of a highly potent compound in ethyl acetate extract with more than 20% increase in the cellular viability of normal human dermal fibroblasts (nHDFs) compared with the negative control amended with DMSO. The subsequent fractionation of the ethyl acetate extract led to two bioactive fractions with high anti-UV property; one of the fractions was further separated down to a single compound. While electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR) spectroscopy analysis identified this single compound as loliolide, its identification has been rarely reported in microalgae previously, prompting thorough systematic investigations into this novel compound for the nascent microalgal industry.

Whitening and moisturizing enhancing effects of three-dimensional human adipose-derived mesenchymal stem cell-conditioned medium-containing cream.

BACKGROUND: High-functional cosmetic products combined with the concept of "treatment" cosmetics are being introduced to the market. Cosmetic products containing a skin-derived microbiome, a three-dimensional (3D) stem cell culture medium, and low-molecular-weight collagen are being introduced, and these products are leading the cosmeceutical market. We aimed to confirm the potential of a 3D stem cell culture medium-containing cream as a skin-whitening and moisturizing product. AIM: To determine the enhancing effects of a cream containing 3D adipose tissue-derived mesenchymal stem cell-conditioned media (3D ADMSC-CM) on whitening and moisturization. METHODS: The inhibitory activities of tyrosinase (TYR) and melanin were confirmed using 3D ADMSC-CM. Furthermore, hyaluronic acid expression in 3D ADMSC-CM was verified. The clinical efficacy of the cream containing 3D ADMSC-CM was established by evaluating its antioxidant properties and effects on skin tone, radiance, freckles, and moisturization. RESULTS: The use of 3D ADMSC-CM suppressed the inhibitory effects of TYR and melanin by approximately 24% and 33%, respectively, and increased the expression of hyaluronic acid synthase. A significant difference was observed after 4 weeks of using 3D ADMSC-CM in the skin antioxidant evaluation. After 2 and 4 weeks of use, skin tone and radiance increased and skin freckles decreased significantly. Under extremely cold and dry weather conditions, the use of the cream increased skin moisturization. CONCLUSIONS: The 3D ADMSC-CM cream evaluated in an environment similar to the human body was found to enhance skin whitening and moisturization and can therefore be used in the skin care and cosmetic industries as a biocosmetic product.

Nodakenin Inhibits Melanogenesis Via the ERK/MSK1 Signaling Pathway.

The aim of the present study was to investigate the potential inhibitory effects of nodakenin, a coumarin glucoside derivative from the root extract of Angelica gigas Nakai (AGN), on melanogenesis and its underlying mechanisms in B16F10 melanoma cells. The inhibitory effects of nodakenin on melanogenesis were evaluated by determining melanin contents and tyrosinase activity in α -melanocyte stimulating hormone (α-MSH)-treated B16F10 melanoma cells. The mechanisms associated with the anti-pigmentation effect of nodakenin were investigated by quantitative real-time PCR and immunoblotting analysis. Using the UVB-irradiated conditioned media culture system and UVB-irradiated co-cultivation system of HaCaT keratinocytes and B16F10 melanoma cells mimicking in vivo melanin biosynthesis, the effect of nodakenin on melanin production was evaluated. Melanin content analysis showed that nodakenin decreased cellular melanin biosynthesis in α-MSH-treated B16F10 cells. Immunoblotting revealed that CREB phosphorylation, MITF, a mastering transcription factor of melanogenesis and its downstream genes tyrosinase, tyrosinase-related protein 1, and tyrosinase-related protein 2 were downregulated by nodakenin in a dose-dependent manner. Interestingly, nodakenin did not affect the phosphorylation of PKA and p38 MAPK but the phosphorylation of ERK1/2 and MSK1. In addition, the inhibition of melanin accumulation by nodakenin in the UVB-irradiated conditioned media culture system and UVB-irradiated co-cultivation system of HaCaT and B16F10 cells suggests that nodakenin has potential as an anti-pigmentation activity. These data suggest that nodakenin inhibits the melanogenesis in B16F10 cells by interfering the ERK/ MSK1/CREB axis and thus preventing MITF expression.

Effects of Allium hookeri Extracts on Hair-Inductive and Anti-Oxidative Properties in Human Dermal Papilla Cells.

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 ß-Catenin and NRF2 translocation into the nucleus while inhibiting the translocation of NF-κB (p50) through p38 and PKA-mediated phosphorylations of GSK3ß, an upstream regulator of those proteins. These results overall indicate the possibility that AHE can regulate GSK3ß-mediated ß-Catenin, NRF2, and NF-κB signaling to enhance hair-inductive properties and ultimately protect against oxidative stress-induced cellular damage in human DPCs.

Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway.

Ovarian cancer is a carcinoma that affects women and that has a high mortality rate. Overcoming paclitaxel resistance is important for clinical application. However, the effect of amino acid metabolism regulation on paclitaxel-resistant ovarian cancer is still unknown. In this study, the effect of an amino acid-deprived condition on paclitaxel resistance in paclitaxel-resistant SKOV3-TR cells was analyzed. We analyzed the cell viability of SKOV3-TR in culture conditions in which each of the 20 amino acids were deprived. As a result, the cell viability of the SKOV3-TR was significantly reduced in cultures deprived of arginine, glutamine, and lysine. Furthermore, we showed that the glutamine-deprived condition inhibited mTORC1/S6K signaling. The decreased cell viability and mTORC1/S6K signaling under glutamine-deprived conditions could be restored by glutamine and α-KG supplementation. Treatment with PF-4708671, a selective S6K inhibitor, and the selective glutamine transporter ASCT2 inhibitor V-9302 downregulated mTOR/S6K signaling and resensitized SKOV3-TR to paclitaxel. Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer.

Melatonin increases growth properties in human dermal papilla spheroids by activating AKT/GSK3ß/ß-Catenin signaling pathway.

Background: Melatonin, a neurohormone, maybe involved in physiological processes, such as antioxidation, anti-inflammation, and hair growth. In the present study, we investigated the effects of melatonin on proliferation and intracellular signaling in DP cells using a three-dimensional (3D) spheroid culture system that mimics the in vivo hair follicle system. Methods: DP cells were incubated in monolayer (2D) and 3D spheroid culture systems. The expression levels of melatonin receptors in DP cells were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. The effect of melatonin on the hair-inductive property of DP cells was analyzed using a WST-1-based proliferation assay, determination of DP spheroid size, expression analysis of DP signature genes, and determination of ß-catenin stabilization in DP cells. The AKT/GSK3ß/ß-catenin signaling pathway associated with melatonin-induced ß-catenin stabilization in DP cells was investigated by analyzing changes in upstream regulator proteins, including AKT, GSK3ß, and their phosphorylated forms. Results: The expression levels of the melatonin receptors were higher in human DP cells than in human epidermal keratinocytes and human dermal fibroblast cells. Comparing the expression level according to the human DP cell culture condition, melatonin receptor expression was upregulated in the 3D culture system compared to the traditional two-dimensional monolayer culture system. Cell viability analysis showed that melatonin concentrations up to 1 mM did not affect cell viability. Moreover, melatonin increased the diameter of DP cell 3D spheroids in a dose-dependent manner. Immunoblotting and qRT-PCR analysis revealed that melatonin upregulated the expression of hair growth-related genes, including alkaline phosphatase, bone morphogenetic protein 2, versican, and wingless-int 5A, in a melatonin receptor-dependent manner. Cell fractionation analysis showed that melatonin increased the nuclear localization of ß-catenin. This result correlated with the increased transcriptional activation of T-cell factor/lymphoid enhancer factor-responsive luciferase induced by melatonin treatment. Interestingly, melatonin induced the phosphorylation of protein kinase B/AKT at serine 473 residue and GSK-3ß at serine 9 residue. To determine whether AKT phosphorylation at serine 473 induced ß-catenin nuclear translocation through GSK3ß phosphorylation at serine 9, the PI3K/AKT inhibitor LY294002 was cotreated with melatonin. Immunoblotting showed that LY294002 inhibited melatonin-induced phosphorylation of GSK3ß at serine 9 residue and ß-catenin activation. Conclusion: Collectively, this report suggests that melatonin promotes growth properties by activating the AKT/GSK3ß/ß-catenin signaling pathway through melatonin receptors.

Daphnetin inhibits α-MSH-induced melanogenesis via PKA and ERK signaling pathways in B16F10 melanoma cells.

Daphnetin is a dehydroxylated derivative of coumarin isolated from Daphne species. However, the effect of daphnetin on melanogenesis has not been elucidated. This study aims to investigate the inhibitory effect of daphnetin on melanogenesis in α-melanocyte stimulating hormone (α-MSH)-treated B16F10 cells and its potential mechanism. Melanin content analysis and cellular tyrosinase activity assay showed that daphnetin inhibited melanin biosynthesis in α-MSH-treated B16F10 cells. Immunoblotting and qRT-PCR also indicated that daphnetin suppressed the expression of microphthalmia-associated transcription factor, a mastering transcription factor of melanogenesis and its downstream melanogenic enzymes including tyrosinase and tyrosinase-related proteins. Moreover, daphnetin downregulated the phosphorylation of PKA, ERK, MSK1, and CREB. Additionally, daphnetin inhibited melanin synthesis in UVB-irradiated HaCaT conditioned medium system suggesting that daphnetin has potential as an antipigmentation activity in a physiological skin condition. Our data propose that daphnetin inhibits melanogenesis via modulating both the PKA/CREB and the ERK/MSK1/CREB pathways.

Diarylpropionitrile inhibits melanogenesis via protein kinase A/cAMP-response element-binding protein/microphthalmia-associated transcription factor signaling pathway in α-MSH-stimulated B16F10 melanoma cells.

Diarylpropionitrile (DPN), a selective agonist for estrogen receptor ß (ERß), has been reported to regulate various hormonal responses through activation of ERß in tissues including the mammary gland and brain. However, the effect of DPN on melanogenesis independent of ERß has not been studied. The aim of this study is to examine the possibility of anti-melanogenic effect of DPN and its underlying mechanism. Melanin contents and cellular tyrosinase activity assay indicated that DPN inhibited melanin biosynthesis in alpha-melanocyte stimulating hormone-stimulated B16F10 melanoma cell line. However, DPN had no direct influence on in vitro tyrosinase catalytic activity. On the other hand, 17ß-estradiol had no effect on inhibition of melanogenesis, suggesting that the DPN-mediated suppression of melanin production was not related with estrogen signaling pathway. Immunoblotting analysis showed that DPN down-regulated the expression of microphthalmia-associated transcription factor (MITF), a central transcription factor of melanogenesis and its down-stream genes including tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2. Also, DPN attenuated the phosphorylation of protein kinase A (PKA) and cAMP-response element-binding protein (CREB). Additionally, DPN suppressed the melanin synthesis in UVB-irradiated HaCaT conditioned media culture system suggesting that DPN has potential as an anti-melanogenic activity in physiological conditions. Collectively, our data show that DPN inhibits melanogenesis via downregulation of PKA/CREB/MITF signaling pathway.

Potential anti-ageing effects of probiotic-derived conditioned media on human skin cells.

In this study, the protective functions of bacteria-free conditioned media from Bifidobacterium and Lactobacillus species against ultraviolet radiation-induced skin ageing and associated cellular damage were investigated. The effects of ultraviolet radiation-induced reactive oxygen species production were suppressed by all conditioned media; particularly, the loss of cell viability and downregulation of collagen gene expression were significantly reversed by the conditioned media from B. longum and B. lactis. Further exa mination of potential anti-pigmentation effects revealed that the B. lactis-derived conditioned media significantly inhibited tyrosinase activity and alpha-melanocyte-stimulating hormone-induced melanin production in human epidermal melanocytes. Further, the conditioned media suppressed the phosphorylation of extracellular signal- related kinase, which functions as an upstream regulator of melanogenesis. Therefore, B. lactis-derived conditioned media can potentially protect against cellular damage involved in skin-ageing processes.

Ginsenoside Rg4 Enhances the Inductive Effects of Human Dermal Papilla Spheres on Hair Growth Via the AKT/GSK-3ß/ß-Catenin Signaling Pathway.

Ginsenoside Rg4 is a rare ginsenoside that is naturally found in ginseng, and exhibits a wide range of biological activities including antioxidant and anti-inflammatory properties in several cell types. The purpose of this study was to use an in vivo model of hair follicle (HF)-mimic based on a human dermal papilla (DP) spheroid system prepared by three-dimensional (3D) culture and to investigate the effect of Rg4 on the hair-inductive properties of DP cells. Treatment of the DP spheroids with Rg4 (20 to 50 µg/ml) significantly increased the viability and size of the DP spheres in a dose-dependent manner. Rg4 also increased the mRNA and protein expression of DP signature genes that are related to hair growth including ALP, BMP2, and VCAN in the DP spheres. Analysis of the signaling molecules and luciferase reporter assays further revealed that Rg4 induces the activation of phosphoinositide 3-kinase (PI3K)/AKT and the inhibitory phosphorylation of GSK3ß, which activates the WNT/ß-catenin signaling pathway. These results correlated with not only the increased nuclear translocation of ß-catenin following the treatment of the DP spheres with Rg4 but also the significant elevation of mRNA expression of the downstream target genes of the WNT/ß-catenin pathway including WNT5A, ß-catenin, and LEF1. In conclusion, these results demonstrated that ginsenoside Rg4 promotes the hair-inductive properties of DP cells by activating the AKT/GSK3ß/ß-catenin signaling pathway in DP spheres, suggesting that Rg4 could be a potential natural therapy for hair growth.

High-Throughput In Vitro Screening of Changed Algal Community Structure Using the PhotoBiobox.

In a previous study, the sequential optimization and regulation of environmental parameters using the PhotoBiobox were demonstrated with high-throughput screening tests. In this study, we estimated changes in the biovolume-based composition of a polyculture built in vitro and composed of three algal strains: Chlorella sp., Scenedesmus sp., and Parachlorella sp. We performed this work using the PhotoBiobox under different temperatures (10-36°C) and light intensities (50-700 µmol/m-2/s-1) in air and in 5% CO2. In 5% CO2, Chlorella sp. exhibited better adaptation to high temperatures than in air conditions. Pearson's correlation analysis showed that the composition of Parachlorella sp. was highly related to temperature whereas Chlorella sp. and Scenedesmus sp. showed negative correlations in both air and 5% CO2. Furthermore, light intensity slightly affected the composition of Scenedesmus sp., whereas no significant effect was observed in other species. Based on these results, it is speculated that temperature is an important factor in influencing changes in algal polyculture community structure (PCS). These results further confirm that the PhotoBiobox is a convenient and available tool for performance of lab-scale experiments on PCS changes. The application of the PhotoBiobox in PCS studies will provide new insight into polyculture-based ecology.

Perphenazine Attenuates the Pro-Inflammatory Responses in Mouse Models of Th2-Type Allergic Dermatitis.

Developing dermatitis therapeutics has been faced with challenges including adverse effects of topical steroid and high cost of new developing drugs. Here, we found the expression levels of dopamine receptor D2 is higher in skin biopsies of dermatitis patients and an oxazolone-induced animal model of dermatitis. We used perphenazine, an FDA-approved dopamine receptor antagonist to determine the therapeutic effect. Two different animal models including 12-o-tetradecanoylphorbol-13-acetate (TPA) and oxazolone (OXA)-induced dermatitis were employed. TPA and OXA-mediated ear swelling was attenuated by perphenazine. Moreover, perphenazine inhibited infiltrated mast cells into lesion area. We found levels of serum IgE, histamine and cytokines are decreased in mice cotreated with perphenazine and OXA compared to OXA-treated mice. Overall, this is a first study showing that the FDA-approved, anti-psychotic drug, perphenazine, alleviates animal models of dermatitis.

Metformin ameliorates animal models of dermatitis.

Metformin, a potent AMPK activator is the most commonly used drug for diabetes. According to recent reports, metformin lowers the risk of diabetic complications and inflammatory diseases. We found the expression levels of AMPK subunits including PRKAA1, PRKAA2, PRKAB1 and PRKAB2 are decreased in skin biopsies of dermatitis patients from multiple datasets. Interestingly, metformin treatment ameliorates dermatitis symptom in animal model of dermatitis using O-tetradecanoylphorbol-13-acetate (TPA). Especially, the levels of epidermis and dermis thickness were decreased by metformin. We found NFκB activity as well as of gene expression associated with collagen synthesis are attenuated by metformin treatment. These results suggest that metformin treatment alleviates animal model of dermatitis.

Nintedanib ameliorates animal model of dermatitis.

Nintedanib, a receptor tyrosine kinase (RTK) inhibitor has been developed as therapeutics for idiopathic pulmonary fibrosis and non-small lung cancer. We found that the expression levels of RTK, especially VEGFR1 is increased in skin biopsies of dermatitis patients from multiple independent datasets. Moreover, VEGFR1 is highly expressed by infiltrated cells in dermis from oxazolone (OXA) treated mice. Interestingly, nintedanib alleviates dermatitis symptom in OXA-induced animal model. Especially, levels of epidermis thickness, infiltrated immune cells including mast cells and eosinophils were decreased from mice cotreated with nintedanib and OXA compared with OXA treated mice. Moreover, serum IgE and Th2 cytokines including IL-4 and IL-13 were decreased by nintedanib treatment. These results suggest an evidence that nintedanib alleviates animal model of dermatitis.

Glucose metabolism regulates expression of hair-inductive genes of dermal papilla spheres via histone acetylation.

Cellular metabolism is one of the crucial factors to regulate epigenetic landscape in various cells including immune cells, embryonic stem cells and hair follicle stem cells. Dermal papilla cells (DP) interact with epithelial stem cells to orchestrate hair formation. Here we show that active DP exhibit robust aerobic glycolysis. We observed decrease of signature genes associated with hair induction by DP in presence of low glucose (2 mM) and glycolysis inhibitors. Moreover, hair shaft elongation was attenuated by glycolysis inhibitors. Interestingly, excessive glucose is able to increase the expression of hair inductive genes and elongation of hair shaft. We also observed glycolysis-mediated histone acetylation is increased and chemical inhibition of acetyltransferase reduces expression of the signature genes associated with hair induction in active DP. These results suggest that glucose metabolism is required for expression of signature genes associated with hair induction. This finding may be beneficial for establishing and maintaining of active DP to generate hair follicle in vitro.