Glycinamide Facilitates Nanocomplex Formation and Functions Synergistically with Bone Morphogenetic Protein 2 to Promote Osteoblast Differentiation In Vitro and Bone Regeneration in a Mouse Calvarial Defect Model.

BACKGROUND: This study aimed to identify glycine analogs conducive to the formation of cell-absorbable nanocomplexes, enhancing collagen synthesis and subsequent osteogenesis in combination with BMP2 for improved bone regeneration. METHODS: Glycine and its derivatives were assessed for their effects on osteogenic differentiation in MC3T3-E1 cells and human bone marrow mesenchymal stem cells (BMSCs) under osteogenic conditions or with BMP2. Osteogenic differentiation was assessed through alkaline phosphatase staining and real-time quantitative polymerase chain reaction (RT-qPCR). Nanocomplex formation was examined via scanning electron microscopy, circular dichroism, and ultraviolet-visible spectroscopy. In vivo osteogenic effects were validated using a mouse calvarial defect model, and bone regeneration was evaluated through micro-computed tomography and histomorphometric analysis. RESULTS: Glycine, glycine methyl ester, and glycinamide significantly enhanced collagen synthesis and ALP activity in conjunction with an osteogenic medium (OSM). GA emerged as the most effective inducer of osteoblast differentiation marker genes. Combining GA with BMP2 synergistically stimulated ALP activity and the expression of osteoblast markers in both cell lines. GA readily formed nanocomplexes, facilitating cellular uptake through strong electrostatic interactions. In an in vivo calvarial defect mouse model, the GA and BMP2 combination demonstrated enhanced bone volume, bone volume/tissue volume ratio, trabecular numbers, and mature bone formation compared to other combinations. CONCLUSION: GA and BMP2 synergistically promoted in vitro osteoblast differentiation and in vivo bone regeneration through nanocomplex formation. This combination holds therapeutic promise for individuals with bone defects, showcasing its potential for clinical intervention.

Skin Color Analysis of Various Body Parts (Forearm, Upper Arm, Elbow, Knee, and Shin) and Changes with Age in 53 Korean Women, Considering Intrinsic and Extrinsic Factors.

Background/Objectives: Skin color is innately determined by race and other genetic factors, and it also undergoes acquired changes due to various intrinsic and extrinsic factors. Previous studies on skin color have mainly focused on the face, and research has recently expanded to other body parts. However, there is limited information about the age-dependent changes in the skin color of these body parts. The purpose of this study is to analyze the differences in skin color between various body parts and the changes in skin color of each body part with age. Methods: This study examined the skin color of 53 Korean women subjects evenly distributed in age from the 20s to 60s on several body parts: forearm, upper arm, elbow (extended or folded), knee (extended or folded), thigh, and shin. The lightness (L*), redness (a*), and yellowness (b*) were measured using a spectrophotometer, and the individual typology angle (ITA°) was calculated from the L* and b* values. The melanin index and erythema index were measured using the mexameter. Results: The results showed that the elbow skin had the lowest L* and ITA° values and the highest a* and b* values among the examined body parts, followed by the knee. The melanin index and erythema index were also high in the skin of these body parts. In the analysis of age-dependent changes in the skin color of various body parts, the forearm skin exhibited the most notable decrease in the L* and ITA° values and increases in the a* and b* values, followed by upper-arm skin. The melanin and erythema indices in the forearm also increased as the subjects aged, whereas those in the elbow and knee rather decreased with age. Conclusions: This study suggests that differences in intrinsic and extrinsic skin aging in various body parts may be expressed as different changes in skin color and raises the need for cosmetic and dermatological research to identify the physiological significance of these changes.

Can Plant Extracts Help Prevent Hair Loss or Promote Hair Growth? A Review Comparing Their Therapeutic Efficacies, Phytochemical Components, and Modulatory Targets.

This narrative review aims to examine the therapeutic potential and mechanism of action of plant extracts in preventing and treating alopecia (baldness). We searched and selected research papers on plant extracts related to hair loss, hair growth, or hair regrowth, and comprehensively compared the therapeutic efficacies, phytochemical components, and modulatory targets of plant extracts. These studies showed that various plant extracts increased the survival and proliferation of dermal papilla cells in vitro, enhanced cell proliferation and hair growth in hair follicles ex vivo, and promoted hair growth or regrowth in animal models in vivo. The hair growth-promoting efficacy of several plant extracts was verified in clinical trials. Some phenolic compounds, terpenes and terpenoids, sulfur-containing compounds, and fatty acids were identified as active compounds contained in plant extracts. The pharmacological effects of plant extracts and their active compounds were associated with the promotion of cell survival, cell proliferation, or cell cycle progression, and the upregulation of several growth factors, such as IGF-1, VEGF, HGF, and KGF (FGF-7), leading to the induction and extension of the anagen phase in the hair cycle. Those effects were also associated with the alleviation of oxidative stress, inflammatory response, cellular senescence, or apoptosis, and the downregulation of male hormones and their receptors, preventing the entry into the telogen phase in the hair cycle. Several active plant extracts and phytochemicals stimulated the signaling pathways mediated by protein kinase B (PKB, also called AKT), extracellular signal-regulated kinases (ERK), Wingless and Int-1 (WNT), or sonic hedgehog (SHH), while suppressing other cell signaling pathways mediated by transforming growth factor (TGF)-ß or bone morphogenetic protein (BMP). Thus, well-selected plant extracts and their active compounds can have beneficial effects on hair health. It is proposed that the discovery of phytochemicals targeting the aforementioned cellular events and cell signaling pathways will facilitate the development of new targeted therapies for alopecia.

Multifaceted Effects of L-Cysteine, L-Ascorbic Acid, and Their Derivatives on the Viability and Melanin Synthesis of B16/F10 Cells under Different Conditions.

The total melanin synthesis in the skin depends on various melanogenic factors, including the number of viable melanocytes, the level of melanogenic enzymes per cell, and the reaction rate of the enzymes. The purpose of this study is to examine the effects of L-cysteine (L-Cys), L-ascorbic acid (L-AA), and their derivatives on the tyrosinase (TYR) activity and autoxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) in vitro and the viability and melanin synthesis of B16/F10 cells under different conditions. L-Cysteinamide (C-NH2), glutathione (GSH), L-Cys, L-AA, and N-acetyl L-cysteine (NAC) inhibited the catalytic activity of TYR in vitro. L-AA, C-NH2, L-ascorbic acid 2-O-glucoside (AAG), and 3-O-ethyl L-ascorbic acid (EAA) inhibited the autoxidation of L-DOPA in vitro. L-DOPA exhibited cytotoxicity at 0.1 mM and higher concentrations, whereas L-tyrosine (L-Tyr) did not affect cell viability up to 3 mM. L-AA, magnesium L-ascorbyl 2-phosphate (MAP), and L-Cys attenuated the cell death induced by L-DOPA. C-NH2 decreased the intracellular melanin level at the basal state, whereas L-AA, MAP, and AAG conversely increased it. C-NH2 reduced the number of darkly pigmented cells via in situ L-DOPA staining, whereas L-AA, MAP, GSH, and AAG increased it. C-NH2 decreased the intracellular melanin level at the alpha-melanocyte-stimulating hormone (α-MSH)-stimulated state, while NAC and GSH increased it. L-AA and C-NH2 decreased the intracellular melanin level at the L-Tyr-stimulated state, but NAC and GSH increased it. L-Ascorbyl tetraisopalmitate (ATI) showed no or minor effects in most experiments. This study suggests that L-AA can either promote or inhibit the different melanogenic factors, and C-NH2 can inhibit the multiple melanogenic factors consistently. This study highlights the multifaceted properties of L-Cys, L-AA, and their derivatives that can direct their therapeutic applications in hyperpigmentation, hypopigmentation, or both disorders.

Therapeutic Potential and Mechanisms of Rosmarinic Acid and the Extracts of Lamiaceae Plants for the Treatment of Fibrosis of Various Organs.

Fibrosis, which causes structural hardening and functional degeneration in various organs, is characterized by the excessive production and accumulation of connective tissue containing collagen, alpha-smooth muscle actin (α-SMA), etc. In traditional medicine, extracts of medicinal plants or herbal prescriptions have been used to treat various fibrotic diseases. The purpose of this narrative review is to discuss the antifibrotic effects of rosmarinic acid (RA) and plant extracts that contain RA, as observed in various experimental models. RA, as well as the extracts of Glechoma hederacea, Melissa officinalis, Elsholtzia ciliata, Lycopus lucidus, Ocimum basilicum, Prunella vulgaris, Salvia rosmarinus (Rosmarinus officinalis), Salvia miltiorrhiza, and Perilla frutescens, have been shown to attenuate fibrosis of the liver, kidneys, heart, lungs, and abdomen in experimental animal models. Their antifibrotic effects were associated with the attenuation of oxidative stress, inflammation, cell activation, epithelial-mesenchymal transition, and fibrogenic gene expression. RA treatment activated peroxisomal proliferator-activated receptor gamma (PPARγ), 5' AMP-activated protein kinase (AMPK), and nuclear factor erythroid 2-related factor 2 (NRF2) while suppressing the transforming growth factor beta (TGF-ß) and Wnt signaling pathways. Interestingly, most plants that are reported to contain RA and exhibit antifibrotic activity belong to the family Lamiaceae. This suggests that RA is an active ingredient for the antifibrotic effect of Lamiaceae plants and that these plants are a useful source of RA. In conclusion, accumulating scientific evidence supports the effectiveness of RA and Lamiaceae plant extracts in alleviating fibrosis and maintaining the structural architecture and normal functions of various organs under pathological conditions.

Insights into How Plant-Derived Extracts and Compounds Can Help in the Prevention and Treatment of Keloid Disease: Established and Emerging Therapeutic Targets.

Keloid is a disease in which fibroblasts abnormally proliferate and synthesize excessive amounts of extracellular matrix, including collagen and fibronectin, during the healing process of skin wounds, causing larger scars that exceed the boundaries of the original wound. Currently, surgical excision, cryotherapy, radiation, laser treatment, photodynamic therapy, pressure therapy, silicone gel sheeting, and pharmacotherapy are used alone or in combinations to treat this disease, but the outcomes are usually unsatisfactory. The purpose of this review is to examine whether natural products can help treat keloid disease. I introduce well-established therapeutic targets for this disease and various other emerging therapeutic targets that have been proposed based on the phenotypic difference between keloid-derived fibroblasts (KFs) and normal epidermal fibroblasts (NFs). We then present recent studies on the biological effects of various plant-derived extracts and compounds on KFs and NFs. Associated ex vivo, in vivo, and clinical studies are also presented. Finally, we discuss the mechanisms of action of the plant-derived extracts and compounds, the pros and cons, and the future tasks for natural product-based therapy for keloid disease, as compared with existing other therapies. Extracts of Astragalus membranaceus, Salvia miltiorrhiza, Aneilema keisak, Galla Chinensis, Lycium chinense, Physalis angulate, Allium sepa, and Camellia sinensis appear to modulate cell proliferation, migration, and/or extracellular matrix (ECM) production in KFs, supporting their therapeutic potential. Various phenolic compounds, terpenoids, alkaloids, and other plant-derived compounds could modulate different cell signaling pathways associated with the pathogenesis of keloids. For now, many studies are limited to in vitro experiments; additional research and development are needed to proceed to clinical trials. Many emerging therapeutic targets could accelerate the discovery of plant-derived substances for the prevention and treatment of keloid disease. I hope that this review will bridge past, present, and future research on this subject and provide insight into new therapeutic targets and pharmaceuticals, aiming for effective keloid treatment.

Differential Effects of Histidine and Histidinamide versus Cysteine and Cysteinamide on Copper Ion-Induced Oxidative Stress and Cytotoxicity in HaCaT Keratinocytes.

Metal chelators are used for various industrial and medical purposes based on their physicochemical properties and biological activities. In biological systems, copper ions bind to certain enzymes as cofactors to confer catalytic activity or bind to specific proteins for safe storage and transport. However, unbound free copper ions can catalyze the production of reactive oxygen species (ROS), causing oxidative stress and cell death. The present study aims to identify amino acids with copper chelation activities that might mitigate oxidative stress and toxicity in skin cells exposed to copper ions. A total of 20 free amino acids and 20 amidated amino acids were compared for their copper chelation activities in vitro and the cytoprotective effects in cultured HaCaT keratinocytes exposed to CuSO4. Among the free amino acids, cysteine showed the highest copper chelation activity, followed by histidine and glutamic acid. Among the amidated amino acids, cysteinamide showed the highest copper chelation activity, followed by histidinamide and aspartic acid. CuSO4 (0.4-1.0 mM) caused cell death in a concentration-dependent manner. Among the free and amidated amino acids (1.0 mM), only histidine and histidinamide prevented the HaCaT cell death induced by CuSO4 (1.0 mM). Cysteine and cysteinamide had no cytoprotective effects despite their potent copper-chelating activities. EDTA and GHK-Cu, which were used as reference compounds, had no cytoprotective effects either. Histidine and histidinamide suppressed the CuSO4-induced ROS production, glutathione oxidation, lipid peroxidation, and protein carbonylation in HaCaT cells, whereas cysteine and cysteinamide had no such effects. Bovine serum albumin (BSA) showed copper-chelating activity at 0.5-1.0 mM (34-68 mg mL-1). Histidine, histidinamide, and BSA at 0.5-1.0 mM enhanced the viability of cells exposed to CuCl2 or CuSO4 (0.5 mM or 1.0 mM) whereas cysteine and cysteinamide had no such effects. The results of this study suggest that histidine and histidinamide have more advantageous properties than cysteine and cysteinamide in terms of alleviating copper ion-induced toxic effects in the skin.

Ascorbic Acid (Vitamin C) as a Cosmeceutical to Increase Dermal Collagen for Skin Antiaging Purposes: Emerging Combination Therapies.

Ascorbic acid (AA) is an essential nutrient and has great potential as a cosmeceutical that protects the health and beauty of the skin. AA is expected to attenuate photoaging and the natural aging of the skin by reducing oxidative stress caused by external and internal factors and by promoting collagen gene expression and maturation. In this review, the biochemical basis of AA associated with collagen metabolism and clinical evidence of AA in increasing dermal collagen and inhibiting skin aging were discussed. In addition, we reviewed emerging strategies that have been developed to overcome the shortcomings of AA as a cosmeceutical and achieve maximum efficacy. Because extracellular matrix proteins, such as collagen, have unique amino acid compositions, their production in cells is influenced by the availability of specific amino acids. For example, glycine residues occupy 1/3 of amino acid residues in collagen protein, and the supply of glycine can be a limiting factor for collagen synthesis. Experiments showed that glycinamide was the most effective among the various amino acids and amidated amino acids in stimulating collagen production in human dermal fibroblasts. Thus, it is possible to synergistically improve collagen synthesis by combining AA analogs and amino acid analogs that act at different stages of the collagen production process. This combination therapy would be useful for skin antiaging that requires enhanced collagen production.

Combination of Glycinamide and Ascorbic Acid Synergistically Promotes Collagen Production and Wound Healing in Human Dermal Fibroblasts.

The purpose of this study is to present a novel strategy to enhance collagen production in cells. To identify amino acid analogs with excellent collagen production-enhancing effects, human dermal fibroblasts (HDFs) were treated with 20 kinds of amidated amino acids and 20 kinds of free amino acids, individually at 1 mM. The results showed that glycinamide enhanced collagen production (secreted collagen level) most effectively. Glycine also enhanced collagen production to a lesser degree. However, other glycine derivatives, such as N-acetyl glycine, N-acetyl glycinamide, glycine methyl ester, glycine ethyl ester, and glycyl glycine, did not show such effects. Glycinamide increased type I and III collagen protein levels without affecting COL1A1 and COL3A1 mRNA levels, whereas transforming growth factor-ß1 (TGF-ß1, 10 ng mL-1) increased both mRNA and protein levels of collagens. Ascorbic acid (AA, 1 mM) increased COL1A1 and COL3A1 mRNA and collagen I protein levels. Unlike TGF-ß1, AA and glycinamide did not increase the protein level of α-smooth muscle actin, a marker of differentiation of fibroblasts into myofibroblasts. The combination of AA and glycinamide synergistically enhanced collagen production and wound closure in HDFs to a level similar to that in cells treated with TGF-ß1. AA derivatives, such as magnesium ascorbyl 3-phosphate (MAP), 3-O-ethyl ascorbic acid, ascorbyl 2-O-glucoside, and ascorbyl tetraisopalmitate, enhanced collagen production, and the mRNA and protein levels of collagens at 1 mM, and their effects were further enhanced when co-treated with glycinamide. Among AA derivatives, MAP had a similar effect to AA in enhancing wound closure, and its effect was further enhanced by glycinamide. Other AA derivatives had different effects on wound closure. This study provides a new strategy to enhance cell collagen production and wound healing using glycinamide in combination with AA.

Identification of p-Coumaric Acid and Ethyl p-Coumarate as the Main Phenolic Components of Hemp (Cannabis sativa L.) Roots.

Hemp (Cannabis sativa L.) contains a variety of secondary metabolites, including cannabinoids, such as psychoactive (-)-trans-Δ9-tetrahydrocannabinol. The present study was conducted to identify the major phenolic components contained in hemp root, which has been relatively under-researched compared to other parts of hemp. The aqueous ethanol extract of hemp roots was fractionated into methylene chloride (MC), ethyl acetate (EA), and water (WT) fractions, and high-performance liquid chromatography with photodiode array detection (HPLC-DAD) analysis was performed. The main ultraviolet (UV)-absorbing phenolic compound contained in the EA fraction was identified as p-coumaric acid by comparing the retention time and UV absorption spectrum with a standard. Silica gel column chromatography was performed to isolate a hydrophobic derivative of p-coumaric acid contained in the MC fraction. Nuclear magnetic resonance (NMR) analysis identified the isolated compound as ethyl p-coumarate. For comparative purposes, ethyl p-coumarate was also chemically synthesized by the esterification reaction of p-coumaric acid. The content of p-coumaric acid and ethyl p-coumarate in the total extract of hemp root was estimated to be 2.61 mg g-1 and 6.47 mg g-1, respectively, by HPLC-DAD analysis. These values correspond to 84 mg Kg-1 dry root and 216 mg Kg-1 dry root, respectively. In conclusion, this study identified p-coumaric acid and ethyl p-coumarate as the main phenolic compounds contained in the hemp roots.

Antioxidant Effects of Korean Propolis in HaCaT Keratinocytes Exposed to Particulate Matter 10.

Air pollution causes oxidative stress that leads to inflammatory diseases and premature aging of the skin. The purpose of this study was to examine the antioxidant effect of Korean propolis on oxidative stress in human epidermal HaCaT keratinocytes exposed to particulate matter with a diameter of less than 10 µm (PM10). The total ethanol extract of propolis was solvent-fractionated with water and methylene chloride to divide into a hydrophilic fraction and a lipophilic fraction. The lipophilic fraction of propolis was slightly more cytotoxic, and the hydrophilic fraction was much less cytotoxic than the total extract. The hydrophilic fraction did not affect the viability of cells exposed to PM10, but the total propolis extract and the lipophilic fraction aggravated the toxicity of PM10. The total extract and hydrophilic fraction inhibited PM10-induced ROS production and lipid peroxidation in a concentration-dependent manner, whereas the lipophilic fraction did not show such effects. High-performance liquid chromatography with photodiode array detection (HPLC-DAD) analysis showed that the hydrophilic fraction contained phenylpropanoids, such as caffeic acid, p-coumaric acid, and ferulic acid, whereas the lipophilic faction contained caffeic acid phenethyl ester (CAPE). The former three compounds inhibited PM10-induced ROS production, lipid peroxidation, and/or glutathione oxidation, and ferulic acid was the most effective among them, but CAPE exhibited cytotoxicity and aggravated the toxicity of PM10. This study suggests that Korean propolis, when properly purified, has the potential to be used as a cosmetic material that helps to alleviate the skin toxicity of air pollutants.

Metabolic Basis and Clinical Evidence for Skin Lightening Effects of Thiol Compounds.

Melanin pigment is a major factor in determining the color of the skin, and its abnormal increase or decrease can cause serious pigmentation disorders. The melanin pigment of the skin is divided into light pheomelanin and dark eumelanin, and a big difference between them is whether they contain sulfur. Melanin synthesis starts from a common reaction in which tyrosine or dihydroxyphenylalanine (DOPA) is oxidized by tyrosinase (TYR) to produce dopaquinone (DQ). DQ is spontaneously converted to leukodopachrome and then oxidized to dopachrome, which enters the eumelanin synthesis pathway. When DQ reacts with cysteine, cysteinyl dopa is generated, which is oxidized to cysteinyl DQ and enters the pheomelanin synthesis pathway. Therefore, thiol compounds can influence the relative synthesis of eumelanin and pheomelanin. In addition, thiol compounds can inhibit enzymatic activity by binding to copper ions at the active site of TYR, and act as an antioxidant scavenging reactive oxygen species and free radicals or as a modulator of redox balance, thereby inhibiting overall melanin synthesis. This review will cover the metabolic aspects of thiol compounds, the role of thiol compounds in melanin synthesis, comparison of the antimelanogenic effects of various thiol compounds, and clinical trials on the skin lightening efficacy of thiol compounds. We hope that this review will help identify the advantages and disadvantages of various thiol compounds as modulators of skin pigmentation and contribute to the development of safer and more effective strategies for the treatment of pigmentation disorders.

Siegesbeckiae Herba Extract and Chlorogenic Acid Ameliorate the Death of HaCaT Keratinocytes Exposed to Airborne Particulate Matter by Mitigating Oxidative Stress.

Airborne particulate matter with a size of 10 µm or less (PM10) can cause oxidative damages and inflammatory reactions in the skin. This study was conducted to discover natural products that are potentially useful in protecting the skin from PM10. Among the hot water extracts of a total of 23 medicinal plants, Siegesbeckiae Herba extract (SHE), which showed the strongest protective effect against PM10 cytotoxicity, was selected, and its mechanism of action and active constituents were explored. SHE ameliorated PM10-induced cell death, lactate dehydrogenase (LDH) release, lipid peroxidation, and reactive oxygen species (ROS) production in HaCaT cells. SHE decreased the expression of KEAP1, a negative regulator of NRF2, and increased the expression of NRF2 target genes, such as HMOX1 and NQO1. SHE selectively induced the enzymes involved in the synthesis of GSH (GCL-c and GCL-m), the regeneration of GSH (GSR and G6PDH), and GSH conjugation of xenobiotics (GSTκ1), rather than the enzymes that directly scavenge ROS (SOD1, CAT, and GPX1). SHE increased the cellular content of GSH and mitigated the oxidation of GSH to GSSG caused by PM10 exposure. Of the solvent fractions of SHE, the n-butyl alcohol (BA) fraction ameliorated cell death in both the absence and presence of PM10. The BA fraction contained a high amount of chlorogenic acid. Chlorogenic acid reduced PM10-induced cell death, LDH release, and ROS production. This study suggests that SHE protects cells from PM10 toxicity by increasing the cellular antioxidant capacity and that chlorogenic acid may be an active phytochemical of SHE.

Identification of L-Cysteinamide as a Potent Inhibitor of Tyrosinase-Mediated Dopachrome Formation and Eumelanin Synthesis.

The purpose of this study is to identify amino acid derivatives with potent anti-eumelanogenic activity. First, we compared the effects of twenty different amidated amino acids on tyrosinase (TYR)-mediated dopachrome formation in vitro and melanin content in dark-pigmented human melanoma MNT-1 cells. The results showed that only L-cysteinamide inhibited TYR-mediated dopachrome formation in vitro and reduced the melanin content of cells. Next, the antimelanogenic effect of L-cysteinamide was compared to those of other thiol compounds (L-cysteine, N-acetyl L-cysteine, glutathione, L-cysteine ethyl ester, N-acetyl L-cysteinamide, and cysteamine) and positive controls with known antimelanogenic effects (kojic acid and ß-arbutin). The results showed the unique properties of L-cysteinamide, which effectively reduces melanin content without causing cytotoxicity. L-Cysteinamide did not affect the mRNA and protein levels of TYR, tyrosinase-related protein 1, and dopachrome tautomerase in MNT-1 cells. L-Cysteinamide exhibited similar properties in normal human epidermal melanocytes (HEMs). Experiments using mushroom TYR suggest that L-cysteinamide at certain concentrations can inhibit eumelanin synthesis through a dual mechanism by inhibiting TYR-catalyzed dopaquinone synthesis and by diverting the synthesized dopaquinone to the formation of DOPA-cysteinamide conjugates rather than dopachrome. Finally, L-cysteinamide was shown to increase pheomelanin content while decreasing eumelanin and total melanin contents in MNT-1 cells. This study suggests that L-cysteinamide has an optimal structure that can effectively and safely inhibit eumelanin synthesis in MNT-1 cells and HEMs, and will be useful in controlling skin hyperpigmentation.

Acetylated Resveratrol and Oxyresveratrol Suppress UVB-Induced MMP-1 Expression in Human Dermal Fibroblasts.

Resveratrol (RES) and oxyresveratrol (OXYRES) are considered and utilized as active ingredients of anti-aging skin cosmetics. However, these compounds are susceptible to oxidative discoloration and unpleasant odor in solutions, limiting their use in cosmetics. Accordingly, RES and OXYRES were chemically modified to acetylated derivatives with enhanced stability, and their anti-aging effect on the skin and detailed molecular mechanism of their acetylated derivatives were investigated. Acetylated RES and OXYRES lost their acetyl group and exerted an inhibitory effect on H2O2-induced ROS levels in human dermal fibroblast (HDF) cells. In addition, RES, OXYRES, and their acetylated derivatives suppressed UVB-induced matrix metalloproteinase (MMP)-1 expression via inhibition of mitogen-activated protein kinases (MAPKs) and Akt/mTOR signaling pathways. Furthermore, RES, OXYRES, and their acetylated derivatives suppressed type I collagen in TPA-treated HDF cells. Collectively, these results suggest the beneficial effects and underlying molecular mechanisms of RES, OXYRES, and their acetylated derivatives for anti- skin aging applications.

Mechanistic Basis and Clinical Evidence for the Applications of Nicotinamide (Niacinamide) to Control Skin Aging and Pigmentation.

Vitamin B3 (nicotinic acid, niacin) deficiency causes the systemic disease pellagra, which leads to dermatitis, diarrhea, dementia, and possibly death depending on its severity and duration. Vitamin B3 is used in the synthesis of the NAD+ family of coenzymes, contributing to cellular energy metabolism and defense systems. Although nicotinamide (niacinamide) is primarily used as a nutritional supplement for vitamin B3, its pharmaceutical and cosmeceutical uses have been extensively explored. In this review, we discuss the biological activities and cosmeceutical properties of nicotinamide in consideration of its metabolic pathways. Supplementation of nicotinamide restores cellular NAD+ pool and mitochondrial energetics, attenuates oxidative stress and inflammatory response, enhances extracellular matrix and skin barrier, and inhibits the pigmentation process in the skin. Topical treatment of nicotinamide, alone or in combination with other active ingredients, reduces the progression of skin aging and hyperpigmentation in clinical trials. Topically applied nicotinamide is well tolerated by the skin. Currently, there is no convincing evidence that nicotinamide has specific molecular targets for controlling skin aging and pigmentation. This substance is presumed to contribute to maintaining skin homeostasis by regulating the redox status of cells along with various metabolites produced from it. Thus, it is suggested that nicotinamide will be useful as a cosmeceutical ingredient to attenuate skin aging and hyperpigmentation, especially in the elderly or patients with reduced NAD+ pool in the skin due to internal or external stressors.

Arbutin as a Skin Depigmenting Agent with Antimelanogenic and Antioxidant Properties.

Arbutin is a compound of hydroquinone and D-glucose, and it has been over 30 years since there have been serious studies on the skin lightening action of this substance. In the meantime, there have been debates and validation studies about the mechanism of action of this substance as well as its skin lightening efficacy and safety. Several analogs or derivatives of arbutin have been developed and studied for their melanin synthesis inhibitory action. Formulations have been developed to improve the stability, transdermal delivery, and release of arbutin, and device usage to promote skin absorption has been developed. Substances that inhibit melanin synthesis synergistically with arbutin have been explored. The skin lightening efficacy of arbutin alone or in combination with other active ingredients has been clinically evaluated. Combined therapy with arbutin and laser could give enhanced depigmenting efficacy. The use of arbutin causes dermatitis rarely, and caution is recommended for the use of arbutin-containing products, especially from the viewpoint that hydroquinone may be generated during product use. Studies on the antioxidant properties of arbutin are emerging, and these antioxidant properties are proposed to contribute to the skin depigmenting action of arbutin. It is hoped that this review will help to understand the pros and cons of arbutin as a cosmetic ingredient, and will lead to future research directions for developing advanced skin lightening and protecting cosmetic products.

Natural Nrf2 Modulators for Skin Protection.

Since the discovery of antioxidant responsive elements (ARE), which are commonly found in the promoter of the Phase II metabolism/antioxidant enzymes, and nuclear factor erythroid 2-related factor 2 (Nrf2), the transcription factor that binds to ARE, the study conducted in this field has expanded remarkably over the decades, and the Nrf2-mediated pathway is now recognized to occupy a central position in cell defense mechanisms. Induction of the Phase II metabolism/antioxidant enzymes through direct activation of Nrf2 can be a promising strategy for preventing degenerative diseases in general, but a dark side of this strategy should be considered, as Nrf2 activation can enhance the survival of cancer cells. In this review, we discuss the historical discovery of Nrf2 and the regulatory mechanism of the Nrf2-mediated pathway, focusing on the interacting proteins and post-translational modifications. In addition, we discuss the latest studies that examined various natural Nrf2 modulators for the protective roles in the skin, in consideration of their dermatological and cosmetic applications. Studies are reviewed in the order of time of research as much as possible, to help understand how and why such studies were conducted under the circumstances of that time. We hope that this review can serve as a steppingstone in conducting more advanced research by providing a scientific basis for researchers newly entering this field.

Up- or Downregulation of Melanin Synthesis Using Amino Acids, Peptides, and Their Analogs.

Harmonious synthesis and distribution of melanin in the skin contribute to the expression of beauty and the maintenance of health. When skin pigmentary disorders occur because of internal or external factors or, when there is a need to artificially increase or reduce the pigmentation level of the skin for aesthetic or therapeutic purposes, various pharmacological therapies are applied but the results are not always satisfactory. Studies have been conducted to improve the efficacy and safety of these treatment strategies. In this review, we present the latest studies regarding peptides and related compounds that may be useful in artificially increasing or reducing skin melanin levels. Certain analogs of α-melanocyte stimulating hormone (MSH) and oligopeptides with the sequences derived from the hormone were shown to promote melanin synthesis in cells and in vivo models. Various amino acids, peptides, their analogs, and their hybrid compounds with other chemical moieties were shown to inhibit tyrosinase (TYR) catalytic activity or downregulate TYR gene expression. Certain peptides were shown to inhibit melanosome biogenesis or induce autophagy, leading to decreased pigmentation. In vivo and clinical evidence are available for some compounds, including [Nle4-D-Phe7]-α-MSH, glutathione disulfide, and glycinamide hydrochloride. For many other compounds, additional studies are required to verify their efficacy and safety in vivo and in clinical trials. The accumulating information regarding pro- and antimelanogenic activity of peptides and related compounds will lead to the development of novel drugs for the treatment of skin pigmentary disorders.

The First Human Clinical Trial on the Skin Depigmentation Efficacy of Glycinamide Hydrochloride.

A previous study identified certain low molecular anti-melanogenic peptides that share a common sequence with α-melanocyte stimulating hormone (MSH) and end with a glycinamide moiety. Glycinamide itself also showed anti-melanogenic activity in cell-based assays, but neither glycine nor acetyl glycinamide were active, which indicated a special structure and activity relationship. The aim of this study was to examine the skin depigmentation efficacy of glycinamide hydrochloride in human subjects. The primary skin irritation potential of glycinamide hydrochloride was evaluated by patch testing in 30 human subjects. The skin depigmentation efficacy of glycinamide hydrochloride was evaluated in a double-blinded clinical test in 21 human subjects. The test product and a control product were applied to designated sites on the right or left side of the face twice daily for eight weeks. Skin color parameters, i.e., the melanin index, the L* value (representing skin lightness), a* value (redness), and b* value (yellowness) were measured using instruments. The individual topology angle (ITAo, representing skin color) was calculated from L* and b values. The degree of skin pigmentation was visually assessed by two testers. The primary skin irritation test showed that a solution containing glycinamide hydrochloride up to 10% did not induce any adverse skin responses. In the efficacy test, the test product significantly reduced the melanin index, and increased L* value and ITAo after two weeks of application relative to the baseline value at the start of the test. It also significantly lowered the degree of pigmentation after 6 weeks of application, relative to the baseline value. Differences in the melanin index, L* value, ITAo and the degree of pigmentation between the test and control groups became statistically significant after six weeks or eight weeks of application. No signs of skin irritation were observed during the efficacy test. The present study suggests that glycinamide hydrochloride has great potential to be used in the control of skin hyperpigmentation.