Article

Caffeic acid induces keratinocyte differentiation by activation of PPAR-α

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Abstract

Peroxisome proliferator-activated receptors (PPAR)-α plays an important role in epidermal differentiation and barrier recovery, and topical treatment with PPAR-α agonists restores epidermal homeostasis in essential fatty acid deficiency and permeability barrier in skin disruptions. Therefore, we performed structure-based pharmacophore screening to search for a novel PPAR-α agonist. Caffeic acid was ultimately selected and evaluated for its effects on keratinocyte differentiation and epidermal permeability barrier. The transactivation activity of PPAR-responsive element (PPRE) and cornified envelope (CE) formation were assayed. Also, immunoblot analysis and anti-oxidant activity were investigated on caffeic acid. Caffeic acid increases the transactivation activity of PPRE and CE formation in keratinocytes. In addition, caffeic acid promotes the expression of genes and proteins related to CE formation such as involucrin and transglutaminase-1. Additionally, anti-oxidant activity were improved by caffeic acid. Caffeic acid can promote keratinocyte differentiation and restore skin barrier homeostasis and is suggested to be an appropriate skin therapeutic agent for improving epidermal permeability barrier function.

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... 9−11 In addition, caffeic acid induces keratinocyte differentiation by activating PPAR-α. 12 Caffeic acid phenethyl ester (CAPE) improves cutaneous wound healing by exerting anti-inflammatory and antioxidant effects. 13,14 Furthermore, topical application of chlorogenic acid facilitates reepithelialization during cutaneous wound healing. ...
... The propolis extract contained physiologically active substances responsible for keratinocyte differentiation and reepithelialization, such as caffeic acid and chlorogenic acid. 12,15 Likewise, artepillin C, baccharin, p-coumaric acid, drupanin, and kaempferide, which suppress tumor cell growth, 28 quantity of kaempferol, which promotes apoptosis in human bladder and ovarian cancer cells. 9,10 Propolis Facilitates Normal Hair Growth in the Shaved-Mouse Model. ...
... 14,21,22,35 In particular, chlorogenic acid and caffeic acid facilitate keratinocyte proliferation and differentiation, respectively. 12,15 The Brazilian propolis ethanol extract used in this study contained both chlorogenic acid (0.7 mg/mL) and caffeic acid (1.3 mg/ mL). Therefore, it is possible that propolis stimulated hair growth in shaved and depilated mice via the effects of its components on hair keratinocyte proliferation and differentiation. ...
Article
Propolis is a natural honeybee hive product with the potential for use in the treatment of dermatological conditions, such as cutaneous abrasions, burns, and acne. In this study, we investigated whether propolis stimulates hair growth in mice. Ethanol-extracted propolis, which contains various physiologically active substances such as caffeic acid and kaempferol, stimulated anagen induction in the shaved back skin. Anagen induction occurred without any detectable abnormalities in the shape of the hair follicles (HFs), hair stem cells in the bulge, proliferating hair matrix keratinocytes in the hair bulb, or in the localization of versican in the dermal papilla. Propolis treatment also stimulated migration of hair matrix keratinocytes into the hair shaft in HFs during late anagen in the depilated back skin. Organotypic culture of skin containing anagen stage HFs revealed significant stimulation of hair matrix keratinocyte proliferation by propolis. Furthermore, propolis facilitated the proliferation of epidermal keratinocytes. These results indicate that propolis stimulates hair growth by inducing hair keratinocyte proliferation.
... Skin aging and such diseases are closely associated with keratinocyte functioning. Keratinocytes play an important role in skin regeneration and barrier functions [24][25][26]. When oxidative stress is excessive, keratinocyte differentiation becomes abnormal [25,27], resulting in an abnormal skin barrier that causes skin diseases and accelerates the overall aging of the skin due to excessive moisture evaporation [28,29]. ...
... As keratinocytes differentiate, the following four layers of structure form in the epidermis: the basal layer, spinous layer, granular layer, and stratum corneum. They play crucial roles in maintaining the skin barrier [24,25]. Therefore, it is important to maintain a normal level of keratinocyte differentiation if one is to sustain a healthy epidermal layer. ...
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... 21 Penelitian lain melaporkan bahwa caffeic acid yang merupakan komponen organik penting pada tanaman obat, sayuran, propolis lebah dan VCo dapat menstimulasi diferensiasi keratinosit dan permeabilitas barrier epidermal yang memiliki efektivitas sebagai antioksidan dan antiinflamasi. 14,17 Protocatechuic acid merupakan komponen alami VCo yang memiliki aktivitas antiinflamasi yang diperantarai oleh pelepasan histamin. 9 ...
... Hasil analisis pada penelitian ini menunjukkan bahwa VCo memiliki target protein FFA yang bertindak sebagai reseptor untuk saturated dan unsaturated fatty acid dengan rantai lemak panjang atau medium.Pada penelitian ini, VCo dapat memperbaiki fungsi barrier kulit (Pa=0,492) dengan prediksi secara komputasi memiliki kemampuan pada aktivitas yang diuji, namun secara uji laboratorium belum terbukti atau memiliki potensi yang kecil. Hal tersebut karena VCo mengandung caffeic acid yang berperan dalam diferensiasi keratinosit dan memperbaiki permeabilitas barrier kulit.17 Dermatitis atopik dikategorikan menjadi dua jenis yaitu tipe intrinsik dan ekstrinsik. ...
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Latar belakang: Analisis in silico digunakan pada tahap awal penelitian dalam penemuan obat baru untuk efisiensi biaya dan waktu. Virgin Coconut Oil (VCO) merupakan salah satu pilihan terapi pada kasus dermatitis atopik karena memiliki fungsi memperbaiki barrier kulit dan antiinflamasi. Tujuan: Untuk mengevaluasi kandungan VCO menggunakan analisis in silico secara komputasional pada pengobatan dermatitis atopik. Metode: Senyawa aktif Cocos nucifera yang diekstraksi dari database KNApSAcK diprediksi secara eksperimental dan dianalisis secara komputasi menggunakan Simplified Molecular-Input Line-Entry System (SMILES), Prediction of Activity Spectra for biologically active Substances (PASS) server, dan Search Tool for Interactions of Chemicals (STITCH). Hasil: Terdapat 19 senyawa aktif yang ditemukan pada VCO. Hasil analisis menunjukkan VCO memiliki target protein free fatty acid (FFA) yang bertindak sebagai reseptor untuk fatty acid saturated dan fatty acid unsaturated dengan rantai lemak panjang atau medium. Potensi bioaktivitas senyawa aktif VCO tertinggi yaitu sebagai antieczema, dengan komponen yang paling berperan adalah linoleic acid dengan rata-rata nilai probable to be active (Pa) 0,872, dan diprediksi memiliki potensi yang tinggi secara komputasi maupun uji laboratorium. Kesimpulan: Berdasarkan penelitian ini kami menyarankan penggunaan VCO sebagai terapi pada dermatitis atopik karena VCO memiliki potensi bioaktivitas antiinflamasi, inhibitor histamin, memperbaiki fungsi barrier kulit dan antieczema sehingga menghambat terjadinya dermatitis atopik.
... Previous studies have reported positive results of wound healing and skin repair by utilizing CM from cultured MSCs (MSC-CM) derived from different sources such as bone marrow mesenchymal stem cell (BM-MSC) [9,12,13], adipose stem cell [14][15][16], Wharton's jelly-derived MSC [17], and human umbilical MSC [1]. Furthermore, numerous studies have proven that several kinds of drugs can be potentially used to promote cell growth and proliferation that is beneficial for wound healing and hair regeneration including UK5099 [18], sodium L-lactate (SLL) [19], lactate dehydrogenase-A (LDHA) [18], caffeine [20,21], and caffeic acid (CFA) [22]. ...
... We found that UK5099, SLL, LDHA, MSC-CM, caffeine, and CFA could promote the proliferation of HFMSC, but only MSC-CM and CFA could promote the proliferation of the HaCaT keratinocyte. Previous study found that caffeic acid produced low cytotoxicity of keratinocytes that can induce cell proliferation and differentiation [22]. Furthermore, another study confirmed that cell proliferation could also be elevated by means of CM from culture MSC [13]. ...
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The study elucidated the wound healing and hair regeneration properties of a conditioned medium prepared from the culture of human hair follicle mesenchymal stem cells (HFMSCs). The wound-healing effects of mesenchymal stem cell-conditioned medium (MSC-CM) were tested in vitro using scratch assays co-cultured with HaCaT keratinocyte and monitored through optical microscopy. The cell proliferation of HFMSCs and the HaCaT keratinocyte were observed in the presence of different kinds of drugs including UK5099, sodium L-lactate, lactate dehydrogenase-A, MSC-CM, caffeine, and caffeic acid. The hair regeneration properties were investigated in vivo by administrating the MSC-CM solutions to adult B6 mouse models. For quantification, hematoxylin and eosin staining were performed following euthanasia. In vitro results revealed that MSC-CM promotes dermal cell migrations and enhances proliferation of HFMSCs and HaCaT keratinocytes, demonstrating wound-healing properties. Moreover, when the MSC-CM solutions were applied to the shaved mouse skin, a dark area that expanded overtime was seen. Although no hair growth was found, histological analysis proved that a fat layer thickness increment was found under the mouse’s skin, ultimately projecting the formation of new hair growth. MSC-CM promotes the migration and proliferation of dermal keratinocytes that are beneficial for wound healing and hair growth. It is believed that MSC-CM can potentially serve as the basis of alternative therapeutic applications for wound closure and skin regeneration as well as hair growth stimulation and hair loss prevention in alopecia.
... To establish a mature skin barrier function mechanically, involucrin and transglutaminase 1 [58] . Other studies demonstrated that caffeic acid induces keratinocyte differentiation via PPAR- activation [59] , and that GW0742, a PPAR- selective activator, induces keratinocyte differentiation and inhibits proliferation [60] . and PPAR (ciglitazone) to hairless mice enhances synthesis of cholesterol, fatty acid and ceramides, and consequently that the activators accelerate the recovery from acute disruption of skin barrier function [62] . ...
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Peroxisome proliferator-activated receptors (PPARs) are fatty acid activated transcription factors that belong to the nuclear hormone receptor family. They are initially known as transcriptional regulators of lipid and glucose metabolism, although further evidence has also been accumulated for other functions. Due to the nature of all PPAR isotypes which are expressed and exert effects by regulating the functions of cell types residing and infiltrating in the skin, PPARs represent a major research target for the understanding and treatment of many skin diseases. Atopic dermatitis (AD) is a chronic and relapsing disease characterized by skin barrier dysfunction and immune dysregulation. Skin barrier disturbance is one of the exacerbation factors of AD, due to facile penetration of molecules such as antigens. From the aspect of immune dysregulation, innate and acquired immunity including cell proliferation, cell differentiation, and cytokine network are involved in the pathogenesis. In this review, the role of PPAR in AD and the possibility of its agonist for the treatment of AD are discussed.
... The enzymes are dominantly expressed in keratinocyte [47] and their expressions are upregulated upon keratinocyte differentiation [48] . Previous studies demonstrated that the activation of PPARs induced keratinocyte differentiation [49,50] . Westergaard and the colleagues showed that L165041, a selective PPAR-/ activator, was the most potent for keratinocyte differentiation, compared with PPAR- and PPAR- activators [26] . ...
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Perturbation of cutaneous homeostasis including immune dysregulation and skin barrier dysfunction evokes skin disorders. In this study, we examined the effect of Eucalyptus citriodora (Euc-c) extract on cytokine production, cell proliferation and cell differentiation in HaCaT cells to elucidate its influence on cutaneous homeostasis. Euc-c suppressed significantly LPS-induced IL-6 and TNF-a-induced IL-8 production from HaCaT cells. Conversely IL-1ra production was significantly enhanced by Euc-c. The expressions of IVL, CERS3 and CERS4, keratinocyte differentiation markers, were upregulated to 3.1, 2.8 and 2.7-fold respectively by Euc-c treatment, compared to the control, while the proliferation was downregulated. The lipid contents in Euc-c-treated cells tended to increase, compared with non-treated cells. To explore the underlying mechanism of these effect, we next performed siRNA experiments against PPAR-b/d. Euc-c enhanced PPAR-b/d mRNA expression to 3.25-fold, while PPAR-b/d mRNA expression in transfected cells was suppressed. The expressions of IVL, CERS3 and CERS4 in transfected cells were suppressed to 1.48, 0.82 and 0.72-fold respectively, concomitant with suppression of PPAR-b/d mRNA expression. These results indicated that Euc-c exerts anti-inflammatory effects and regulates keratinocyte differentiation via the modulation of PPAR-b/d pathway. Therefore, the application of Euc-c is expected to exert beneficial effect on skin disorders evoked by perturbation of skin homeostasis.
... To establish a mature skin barrier function mechanically, involucrin and transglutaminase 1 [58] . Other studies demonstrated that caffeic acid induces keratinocyte differentiation via PPAR- activation [59] , and that GW0742, a PPAR- selective activator, induces keratinocyte differentiation and inhibits proliferation [60] . and PPAR (ciglitazone) to hairless mice enhances synthesis of cholesterol, fatty acid and ceramides, and consequently that the activators accelerate the recovery from acute disruption of skin barrier function [62] . ...
Article
Full-text available
Peroxisome proliferator-activated receptors (PPARs) are fatty acid activated transcription factors that belong to the nuclear hormone receptor family. They are initially known as transcriptional regulators of lipid and glucose metabolism, although further evidence has also been accumulated for other functions. Due to the nature of all PPAR isotypes which are expressed and exert effects by regulating the functions of cell types residing and infiltrating in the skin, PPARs represent a major research target for the understanding and treatment of many skin diseases. Atopic dermatitis (AD) is a chronic and relapsing disease characterized by skin barrier dysfunction and immune dysregulation. Skin barrier disturbance is one of the exacerbation factors of AD, due to facile penetration of molecules such as antigens. From the aspect of immune dysregulation, innate and acquired immunity including cell proliferation, cell differentiation, and cytokine network are involved in the pathogenesis. In this review, the role of PPAR in AD and the possibility of its agonist for the treatment of AD are discussed.
... 84 Acetoside is a phenylpropanoid consisted of three moieties of caffeic acid, tyrosol linked by rutinose, while caffeic acid itself is known as PPAR-α agonist. 85 Acetoside itself exerted its antiinflammatory effect by PPAR-mediated mechanism. 86 The anthocyanin peonidin 3-3-(6v-p-coumarylglucoside) consists of cyanidin linked to p-coumaric acid by glucose; interestingly, anthocyanins and cyanidins were reported to be agonist to PPAR-α. ...
Chapter
Olea Europaea is an evergreen tree used for centuries to produce oil, diet and medicines. The Olive leaves extract was investigated thoroughly to identify its phytochemical components and its bioactivities, since it showed remarkable pharmacological effect for prevention and treatment experimentally induced metabolic diseases such as cataract , we decided to reveal how active constituents found in olive leaves extract exert (OLE) their actions using in-silico tools and literature survey. The in-silico studies showed the ability of several compounds in OLE to inhibit multiple pathways that contribute in cataract formations such as Proliferator peroxisome activated receptor alpha, aldose reductase and Calpain-1, which was supported by several studies that also showed that OLE polyphenolic prevent Advanced glycation end products formation. Since the control of metabolic diseases usually require more than therapeutic agent, it’s safe to consider OLE as a perfect candidate, however more clinical trials are needed to ensure its safety and effectiveness
... The antioxidant effect of CA-PH may affect the stratum corneum and keratinocytes, resulting in skin barrier function recovery. In addition, caffeic acid itself promotes involucrin expression 32 . Each protein was immunostained with dark brown color (indicated by black arrows; scale bar, 100 μm). ...
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... The enzymes are dominantly expressed in keratinocyte [47] and their expressions are upregulated upon keratinocyte differentiation [48] . Previous studies demonstrated that the activation of PPARs induced keratinocyte differentiation [49,50] . Westergaard and the colleagues showed that L165041, a selective PPAR-/ activator, was the most potent for keratinocyte differentiation, compared with PPAR- and PPAR- activators [26] . ...
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Full-text available
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... with several skin diseases including psoriasis, atopic dermatitis and ichthyosis vulgaris [16,27,28]. ...
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Summary Our recent studies have demonstrated that PPAR activators stimulate differentiation and inhibit proliferation in cultured human keratinocytes and accelerate epidermal development and permeability barrier formation in fetal rat skin explants. As the role of PPAR activation in adult epidermis is not known, the aim of this study was to determine if topically applied PPAR ligands regulate keratinocyte differentiation in murine epidermis. Topical treatment with PPAR activators resulted in decreased epidermal thickness. Expression of structural proteins of the upper spinous/granular layers (involucrin, profilaggrin-filaggrin, loricrin) increased following topical treatment with PPAR activators. Furthermore, topically applied PPAR activators also increased apoptosis, decreased cell proliferation, and accelerated recovery of barrier function following acute barrier abrogation. Experiments with PPAR–/– knockout mice showed that these effects are specifically mediated via PPAR. Compared with the epidermis of PPAR+/+ mice, involucrin, profilaggrin-filaggrin, and loricrin expression were slightly decreased in PPAR–/– mice. Moreover, topical clofibrate treatment did not increase epidermal differentiation in PPAR–/– mice. Furthermore, in cultured human keratinocytes we have demonstrated that PPAR activators induce an increase in involucrin mRNA levels. We have also shown that this increase in gene expression requires an intact AP-1 response element at -2117 to -2111 bp. Thus, stimulation of PPAR stimulates keratinocyte/epidermal differentiation and inhibits proliferation.
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In this study, we investigated whether dietary glucosylceramide (GlcCer) and its metabolite sphingoid bases, sphingosine (SS), phytosphingosine (PS), sphingadienine (SD) and 4-hydroxysphingenine (4HS), influence cornified envelope (CE) formation. CE is formed during terminal differentiation of the epidermis through crosslinking of specific precursor proteins by transglutaminases (TGases), and is essential for the skin's barrier function. Oral administration of GlcCer (0.25 mg/day) for 14 consecutive days dramatically reduced transepidermal water loss, an indicator of the skin barrier condition, in hairless mice with barrier perturbation induced by single-dose ultraviolet B (UVB) irradiation. The GlcCer treatment also increased the level of TGase-1 mRNA in UVB-irradiated murine epidermis approximately 1.6-fold compared with the control. Further, all four sphingoid bases at 1 μM concentration enhanced CE formation of cultured normal human keratinocyte cells. Among them, SS, PS and SD, but not 4HS, stimulated production of involucrin, one of the CE major precursor proteins. SD increased the expression of TGase-1 mRNA, while SS increased the expression of TGase-3 mRNA. These results indicate that the skin barrier improvement induced by oral GlcCer treatment might be at least partly due to a reinforcement of CE formation in the epidermis mediated by sphingoid bases metabolically derived from GlcCer.
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Phenolics are ubiquitous compounds found in all plants as their secondary metabolites. These include simple phenols, hydroxybenzoic acid and cinnamic acid derivatives, flavonoids, coumarines and tannins, among others. The extraction of phenolics from source materials is the first step involved in their analysis. While chemical methods are used for determination of total content of phenolics, chromatographic and spectrometric analyses are employed for identification and quantification of individual compounds present. This paper provides a summary of background information and methodologies used for the analysis of phenolics in foods and nutraceuticals.
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Objectives: The risk for cardiovascular disease is significantly high in diabetes mellitus. Experimental evidence suggests that oxidative stress plays a dominant role in the pathogenesis of diabetes mellitus. Caffeic acid phenethyl ester (CAPE), an active component of propolis, has several biological and pharmacological properties, including antioxidant, anti-inflammatory, anti-carcinogenic, antiviral, and immunomodulatory activities. In light of the antioxidant ability of CAPE, the effects of CAPE on the antioxidative status of cardiac tissue were investigated in streptozotocin (STZ)-induced diabetic rats. Design and methods: Twenty-six rats were randomly divided into three groups: group I, control, nondiabetic rats (n = 9); group II, STZ-induced, untreated diabetic rats (n = 7); and group III, STZ-induced, CAPE-treated diabetic rats (n = 10). In groups II and III, diabetes developed 3 days after intraperitoneal (ip) administration of a single 35 mg kg(-1) dose of STZ. Thereafter, while the rats in group II received no treatment, the rats in group III began to receive a 10 mumol kg(-1) ip dose of CAPE per day. After 8 weeks, the levels of malondialdehyde (MDA) and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the cardiac tissues of all groups were analyzed. Results: In untreated diabetic rats, MDA markedly increased in the cardiac tissue compared with the control rats (P < 0.05). However, MDA levels were reduced to the control level by CAPE. The activities of SOD and CAT in the untreated diabetic group and the CAPE-treated diabetic group were higher than those of the control group (P < 0.05). Rats in the CAPE-treated diabetic group had reduced activities of SOD and CAT in comparison with the rats in the untreated diabetic group (P < 0.05). There were no significant differences in the activity of GSH-Px between the rats in the untreated diabetic group and the control group. However, the activity of GSH-Px was increased in CAPE-treated diabetic rats compared with the control and untreated diabetic rats (P < 0.05). Conclusion: These results reveal that diabetes mellitus increases oxidative stress in cardiac tissue and CAPE has an ameliorating effect on the oxidative stress via its antioxidant property.
Article
Most epidermal functions can be considered as protective, or more specifically, as defensive in nature. Yet, the term "barrier function" is often used synonymously with only one such defensive function, though arguably its most important, i.e., permeability barrier homeostasis. Regardless of their relative importance, these protective cutaneous functions largely reside in the stratum corneum (SC). In this review, I first explore the ways in which the multiple defensive functions of the SC are linked and interrelated, either by their shared localization or by common biochemical processes; how they are co-regulated in response to specific stressors; and how alterations in one defensive function impact other protective functions. Then, the structural and biochemical basis for these defensive functions is reviewed, including metabolic responses and signaling mechanisms of barrier homeostasis. Finally, the clinical consequences and therapeutic implications of this integrated perspective are provided.
Article
Caffeic acid (3,4-dihydroxycinnamic acid) is among the major hydroxycinnamic acids present in wine; sinapic acid, which is a potent antioxidant. It has also been identified as one of the active antioxidant. In the present study, the antioxidant properties of the caffeic acid were evaluated by using different in vitro antioxidant assays such as 2-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical scavenging, 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH) scavenging, total antioxidant activity by ferric thiocyanate method, total reductive capability using the potassium ferricyanide reduction method, superoxide anion radical scavenging and metal chelating activities. alpha-Tocopherol, trolox, a water-soluble analogue of tocopherol, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT) were used as the reference antioxidant compounds. At the concentrations of 10 and 30 microg/mL, caffeic acid showed 68.2 and 75.8% inhibition on lipid peroxidation of linoleic acid emulsion, respectively. On the other hand, 20 microg/mL of standard antioxidant such as BHA, BHT, alpha-tocopherol and trolox indicated an inhibition of 74.4, 71.2, 54.7 and 20.1% on peroxidation of linoleic acid emulsion, respectively. In addition, caffeic acid is an effective ABTS(+) scavenging, DPPH scavenging, superoxide anion radical scavenging, total reducing power and metal chelating on ferrous ions activities.
Article
Peroxisome proliferators activated receptors (PPARs) are a family of nuclear hormone receptors that heterodimer with the retinoid X receptor and function as transcriptional regulators of genes. Topically Applied PPAR-alpha agonists possess receptor mediated, pro-differentiating/anti-proliferative effects, lipid metabolism stimulation, and anti-inflammatory activity, which suggest that they could be beneficial for the treatment of a variety of cutaneous diseases. Hyaluronan (HA), a high-molecular-weight linear glycosaminoglycan consisting of alternating D: -glucuronic acid and N-acetyl-D: -glucosamine residues, is one of the major extracellular matrix components in skin. Among the family of HA synthase genes (HAS1, 2, 3) so far identified, one group has demonstrated that the expressions of HAS2 and HAS3 play crucial roles in the regulation of HA synthesis in human skin fibroblasts and keratinocytes, respectively, but the precise regulatory mechanisms are still unknown. We examine Musk T called Ethylene brassylate, Astratone or 1,4-Dioxacycloheptadecane-5,17-dione, which used as just a perfume ingredient, plays a role as PPAR-alpha ligand in vitro and stimulates skin barrier recovery, ceramide synthesis, beta-Glucocerebrosidase, involucrin expression in epidermis in vivo; and examine that Musk T stimulates HAS expression and HA synthesis in human skin fibroblast. Through these experiments, we conclude that Musk T is PPAR-alpha ligand, effects on keratinocyte differentiation, intercellular lipid synthesis in epidermis, HA synthesis stimulation in dermis.
Article
Ursolic acid (UA) and oleanolic acid (ONA) are pentacyclic triterpenoids, which naturally occur in many medicinal herbs and plants. Recent research revealed that several pharmacological effects could be attributed to UA and ONA, such as anti-tumor, anti-inflammatory and anti-microbial activities. To evaluate the effects of UA and ONA on epidermal permeability barrier recovery and normal skin, both flanks of hairless mice were topically treated with either 0.01-0.1 mg/mL UA or 0.1-1.0 mg/mL ONA after tape stripping and transepidermal water loss (TEWL) were assessed, and then hydration and TEWL were measured for 3 weeks with application of UA and ONA (2 mg/mL). We also investigated the morphological changes using light (LM) and electron microscopic (EM) examination. Finally, we observed that UA and ONA stimulated epidermal keratinocyte differentiation via peroxisome proliferator-activated receptor (PPAR)-alpha using Western immunoblotting. The recovery rate of epidermal permeability barrier after tape stripping increased in the UA- and ONA-treated groups (0.1 mg/mL UA and 0.5 mg/mL ONA) at 6 h to more than 20% when compared to the vehicle-treated group (P < 0.05). In both groups, hydration was increased compared to the vehicle group from 1 week without TEWL alteration (P < 0.05). An LM finding showed that epidermal thickening was frequently observed (UA > ONA > vehicle). EM examination revealed an increase in secretion and in the number of lamellar bodies in treated groups and that complete formation of lipid bilayers was also prominent (ONA > UA > vehicle). Protein expression of PPAR-alpha, involucrin, loricrin and filaggrin increased twofold and threefold in HaCaT cells treated for 24 h with either ONA (10 micromol/L) or UA (10 micromol/L), respectively, reflecting that the UA and ONA can improve the recovery of skin barrier function and induce epidermal keratinocyte differentiation via PPAR-alpha. Taken together, these results suggest that UA and ONA will be pertinent candidates for the improvement of epidermal permeability barrier function.
The Effect of caffeic acid on wound healing in skin-incised mice Bora Kim et al. PPAR-α activation by caffeic acid © 2013 Royal Pharmaceutical Society
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