Tranexamic acid inhibits melanogenesis partially via stimulation of TGF-ß1 expression in human epidermal keratinocytes.

Oral tranexamic acid (TA) has been an effective treatment for melasma with unclear mechanism. The present study aimed to demonstrate the effect of TA on melanogenesis via regulation of TGF-ß1 expression in keratinocytes. We firstly determined the expression level of TGF-ß1 in TA-treated keratinocyte-conditioned medium (KCM). Then, the mRNA and protein levels of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR) and tyrosinase-related protein 1 (TRP-1) of human epidermal melanocytes (NHEMs) in the presence of TA-treated KCM were evaluated via RT-PCR and western blot analysis. Moreover, melanin content and tyrosinase activity were quantified. TGF-ß1 gene was knocked down by small interfering RNA (siRNA) in keratinocytes. The mRNA and protein levels of TGF-ß1 in keratinocytes were significantly increased after TA treatment. Melanin contents, tyrosinase activity, protein and mRNA levels of TYR, MITF and TRP-1 were downregulated in NHEMs in the presence of TA-treated KCM. Knockdown of TGF-ß1 in keratinocytes could attenuate the inhibitory effect of TA-treated KCM on melanogenesis. TA could stimulate TGF-ß1 expression in keratinocytes, which further inhibits melanogenesis through the paracrine signalling.

Photobiomodulation Using 830 nm Lighting-Emitting Diode Inhibits Melanogenesis via FOXO3a in Human Melanocyte.

Photobiomodulation (PBM) using 830 nm light-emitting diode (LED) benefits tissue regeneration, wound healing and neural stimulation. However, there is not much exploration of its effect on melanocytes and ex vivo skin model. This study aims to investigate the mechanism behind the anti-melanogenic activity of 830 nm LED and provides evidence for its activity in human ex vivo skin model. Our results showed that 830 nm LED at fluences ranging from 5 to 20 J/cm2 inhibited melanosome maturation and reduced melanin content, tyrosinase activity and melanogenesis-related proteins. 830 nm LED inhibited the phosphorylation of AKT and its downstream FOXO3a, leading to nuclear translocation of FOXO3a. Furthermore, FOXO3a knockdown and AKT activator like SC79 could reverse the melanogenesis inhibition phenotype induced by 830 nm LED. In human ex vivo skin model, Fontana-Masson staining revealed a decrease in epidermal basal pigmentation after 830 nm LED irradiation. Taken together, 830 nm LED demonstrated the anti-melanogenic activity via FOXO3a.

The Emerging Role of Visible Light in Melanocyte Biology and Skin Pigmentary Disorders: Friend or Foe?

Electromagnetic radiation, notably visible light (VL), has complicated effects on human skin, particularly pigmentation, which have been largely overlooked. In this review, we discuss the photobiological mechanisms, pathological effects, clinical applications and therapeutic strategies of VL at varying wavelengths on melanocyte biology and skin pigmentary disorders. Different VL wavelengths may impose positive or negative effects, depending on their interactions with specific chromophores, photoaging, ROS production, circadian rhythm and other photon-mediated reactions. Further in vivo and in vitro studies are required to establish the pathologic mechanisms and application principles of VL in pigmentary disorders, as well as optimal photoprotection with coverage against VL wavelengths.

Cannabidiol Inhibits Inflammation Induced by Cutibacterium acnes-Derived Extracellular Vesicles via Activation of CB2 Receptor in Keratinocytes.

Background: Acne is a common inflammatory skin disease, while cannabidiol (CBD) is a representative non-psychoactive phytocannabinoid which has been proved to exert universal anti-inflammatory properties. This study aimed to explore the effect of CBD on acne inflammation induced by Cutibacterium acnes-derived extracellular vesicles (CEVs) in keratinocytes and reveal the underlying mechanisms. Methods: Normal human epidermal keratinocytes (NHEKs) were stimulated by CEVs in the presence of CBD or vehicle. Interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α levels were examined by RT-PCR and ELISA. The expression of cannabinoid type-2 (CB2) receptor and transient receptor potential vanilloid type-1 (TRPV1) was detected by Western blotting. TNF-α levels in the presence of CB2 receptor antagonist (AM630) or TRPV1 antagonist (Capsazepine) were detected by RT-PCR. The activation of MAPK and NF-κB signaling pathways and the nuclear translocation of NF-κB p65 upon CBD treatment were analyzed by Western blotting and immunofluorescence assay, respectively. Results: The expression of inflammatory cytokines (IL-6, IL-8 and TNF-α) in CEVs-stimulated NHEKs was suppressed by CBD. CB2 receptor expression was upregulated by CBD, whereas CEVs-promoted TRPV1 expression was downregulated by CBD. AM630 reversed TNF-α levels inhibited by CBD. Capsazepine exerted an inhibitory effect on CEVs-induced inflammation and had synergistic effect with CBD. The phosphorylation of ERK1/2 and NF-κB p65 and nuclear translocation of NF-κB p65 were induced by CEVs but reduced by CBD. Conclusion: The results indicated that CBD could inhibit inflammation induced by CEVs in NHEKs, which was mediated by activation of CB2 receptor and enhanced by the TRPV1 antagonist, through inactivation of the MAPK and NF-κB signaling pathways. CBD might be a potential novel strategy for acne treatment in the future.

590 nm LED Irradiation Improved Erythema through Inhibiting Angiogenesis of Human Microvascular Endothelial Cells and Ameliorated Pigmentation in Melasma.

Melasma is a common refractory acquired pigmentary skin disease that mainly affects middle-aged women. The pathogenesis of melasma is still uncertain, while abnormal vascular endothelial cells may play a role. We previously demonstrated the yellow light of light-emitting diodes (LED) could inhibit melanogenesis through the photobiomodulation (PBM) of melanocytes and keratinocytes. In the current study, we investigated the effect of 590 nm LED on the function of human microvascular endothelial cells (HMEC-1). We revealed 0-40 J/cm2 590 nm LED had no toxic effect on HMEC-1 in vitro. 590 nm LED irradiation significantly reduced cell migration, tube formation, as well as the expression of vascular endothelial growth factor (VEGF) and stem cell factor (SCF), a pro-melanogenic factor. Moreover, we illustrated that 590 nm LED inhibited the phosphorylation of the AKT/PI3K/mTOR signaling pathway, and the inhibitory effect on HMEC-1 could be partially reversed by insulin-like growth factor 1 (IGF-1), an AKT/PI3K/mTOR pathway agonist. Besides, we conducted a pilot clinical study and observed a marked improvement on facial erythema and pigmentation in melasma patients after amber LED phototherapy. Taken together, 590 nm LED inhibited HMEC-1 migration, tube formation and the secretion of VEGF and SCF, predominantly through the inhibition of the AKT/PI3K/mTOR pathway, which may serve as a novel therapeutic option for melasma.

Altered expression of ferroptosis markers and iron metabolism reveals a potential role of ferroptosis in vitiligo.

Oxidative stress is one of the triggering factors for vitiligo, which leads to melanocyte (MC) destruction in vitiligo lesions. Ferroptosis, which is characterized by iron-dependent increase in oxidative stress and lipid peroxidation, has been widely explored in numerous diseases, whereas whether ferroptosis plays a role in MC loss of vitiligo remains to be elucidated. Quantitative real-time PCR and western blot analysis were used to determine the expression of ferroptosis markers in vitiligo patients. Immunonephelometry and electrochemiluminescence were performed to analyze iron status. Reactive oxygen species (ROS), Fe2+ , and lipid ROS were assessed by flow cytometry. The expression of ferroptosis markers was significantly altered in the epidermis of vitiligo patients. Iron deficiency was revealed in the blood of patients. Erastin reduced cell viability and led to oxidative stress, iron overload as well as lipid peroxide accumulation in human epidermal MCs in vitro. Altered expression of ferroptosis markers and inhibition of melanin synthesis in MCs were induced by erastin, which was attenuated by N-acetyl-L-cysteine (NAC) pretreatment or post-treatment in vitro. In conclusion, ferroptosis might take place during the process of vitiligo. Erastin could induce ferroptosis in human epidermal MCs and NAC could protect MCs from ferroptosis in vitro.

The efficacy and safety of topical tranexamic acid (liposomal or lotion with microneedling) versus conventional hydroquinone in the treatment of melasma.

BACKGROUND: Robust evidence regarding the efficacy of topical tranexamic acid (TA) on melasma in Chinese population is lacking. OBJECTIVE: To evaluate the efficacy and safety of 1.8% liposomal TA and microneedling with 5% TA solution on melasma. METHODS: Sixty melasma patients were enrolled and randomized to receive 1.8% liposomal TA twice daily, microneedling with 5% TA solution weekly or 2% hydroquinone every night. Objective and subjective assessments were obtained at baseline, 4, 8, and 12 weeks. RESULTS: 27.8% of patients of liposomal TA group, 33.3% of microneedling with TA solution group, and 30.0% of hydroquinone group were recognized as "more than 50% improvement." At the endpoint, the melanin index (MI) in all treatment groups was significantly decreased, while the improvement of MI in microneedling with TA solution group and hydroquinone group is higher than liposomal TA group. The erythema index (EI) was significantly diminished in liposomal TA group and microneedling with TA solution group. Dermatoscopy and reflectance confocal microscopy revealed decreased brown granules in all groups and reduced telangiectasia in liposomal TA group and microneedling with TA solution group. CONCLUSION: 1.8% liposomal TA and microneedling with 5% TA solution are both effective and safe on melasma.

585 nm light-emitting diodes inhibit melanogenesis through upregulating H19/miR-675 axis in LEDs-irradiated keratinocytes by paracrine effect.

BACKGROUND: 585 nm light-emitting diodes have been proven to suppress melanogenesis in melanocytes. However, whether LEDs will influence normal human epidermal keratinocytes (NHEKs) and paracrine effect of LEDs-irradiated NHEKs in melanogenesis remains unknown. OBJECTIVE: To elucidate the possible mechanisms in vitro of anti-melanogenic activity of 585 nm LEDs on paracrine effect of NHEKs and its exosomes. METHODS: NHEKs irradiated with different fluences of 585 nm LEDs were evaluated the cell viability by CCK8 assay. Irradiated medium of NHEKs was co-cultured with melanocytes. Melanin content, tyrosinase activity and melanogenic enzymes activities were detected. Exosomes from NHEKs medium were isolated and characterized by electron microscopy and nanoparticle tracking analysis. The expression changes of H19 and its encoded exosomal miR-675 were analyzed. RESULTS: Irradiation with 585 nm LEDs from 0 J/cm2 to 20 J/cm2 had no cytotoxic effect on NHEKs. After co-cultured with irradiated medium of NHEKs, melanin content and tyrosinase activity were reduced and the melanogenic activities were downregulated on both mRNA and protein levels of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR) and tyrosinase-related protein 1 (TRP-1). H19 and its derived exosomal miR-675 from NHEKs, which has been proven relevant to melanogenesis, were significantly upregulated after irradiation. Furthermore, H19 knockdown and miR-675 inhibition in NHEKs could attenuate the inhibition effect of 585 nm LEDs on melanogenesis. CONCLUSIONS: This study demonstrated that 585 nm LEDs could inhibit melanogenesis via the up-regulation of H19 and its derived exosomal miR-675 from NHEKs, which was considered as a novel paracrine factor in regulating melanogenesis.

Rapid Improvement in Refractory Acute Generalized Exanthematous Pustulosis With Spesolimab.

This case report describes a woman in her 50s with rapid improvement in acute generalized exanthematous pustulosis symptoms after treatment with spesolimab.