Senescent fibroblasts progressively deteriorate the functional properties of skin tissue. Senesce... more Senescent fibroblasts progressively deteriorate the functional properties of skin tissue. Senescent cells secrete senescence-associated secretory phenotype (SASP) factor, which causes the aging of surrounding non-senescent cells and accelerates aging in the individuals. Recent findings suggested the senomorphic targeting of the SASP regulation as a new generation of effective therapeutics. We investigated whether Isatis tinctoria L. leaf extract (ITE) inhibited senescence biomarkers p53, p21CDKN1A, and p16INK4A gene expression, and SASP secretions by inhibiting cellular senescence in the replicative senescent human dermal fibroblast (RS-HDF). ITE has been demonstrated to inhibit the secretion of SASP factors in several senomorphic types by regulating the MAPK/NF-κB pathway via its inhibitory effect on mTOR. ITE suppressed the inflammatory response by inhibiting mTOR, MAPK, and IκBα phosphorylation, and blocking the nuclear translocation of NF-κB. In addition, we observed that autoph...
Inflammation is increasingly recognized as a critical mediator of angiogenesis, and unregulated a... more Inflammation is increasingly recognized as a critical mediator of angiogenesis, and unregulated angiogenic responses often involve human diseases. The importance of regulating angiogenesis in inflammatory diseases has been demonstrated through some successful cases of anti-angiogenesis therapies in related diseases, including arthritis, but it has been reported that some synthetic types of antiangiogenic drugs have potential side effects. In recent years, the importance of finding alternative strategies for regulating angiogenesis has begun to attract the attention of researchers. Therefore, identification of natural ingredients used to prevent or treat angiogenesis-related diseases will play a greater role. Isookanin is a phenolic flavonoid presented in Bidens extract, and it has been reported that isookanin possesses some biological properties, including antioxidative and anti-inflammatory effects, anti-diabetic properties, and an ability to inhibit α-amylase. However, its antiang...
Inflammaging refers to chronic, lowgrade inflammation that contributes to the aging process. A gr... more Inflammaging refers to chronic, lowgrade inflammation that contributes to the aging process. A growing number of references specify that aging is driven by proinflammatory cytokines produced by the innate immune system which involve the inflammasome and Nfkb pathways. These two pathways are interconnected and share a common inducer, the double-stranded RNA-dependent protein kinase PKR. Recently, we showed that inflammation is controlled by an epigenetic process involving PKR and the long noncoding RNA lnc886. Lnc886 regulates inflammation by the direct inhibition of PKR phosphorylation. Although the literature suggests that excessive inflammasome activity leads to inflammaging in age-related pathologies, this has not been not demonstrated for skin aging. The present paper effectively illustrates that along with aging and concomitantly with decreased expression of lnc886 (the PKR inhibitor), the inflammasome is activated. Using several innovative inflammasome models, we demonstrate t...
27 For screening of skin-whitening ingredients that modulate inhibition of melanogenesis, 28 tyro... more 27 For screening of skin-whitening ingredients that modulate inhibition of melanogenesis, 28 tyrosinase promoter-based assay using a 3D spheroid culture technique is a beneficial tool to 29 improve the accuracy of raw material screening in cosmetics through mimicking of the in 30 vivo microenvironment. Although the advantages of high-throughput screening (HTS) are 31 widely known, there has been little focus on specific cell-based promoter assays for HTS in 32 identifying skin-whitening ingredients that inhibit accumulation of melanin. The aim of this 33 study was therefore to develop a large-scale compatible assay through pTyr-EGFP, an 34 enhanced green fluorescent protein (EGFP)-based tyrosinase-specific promoter, to seek 35 potential melanogenesis inhibitors for cosmetic use. Herein, a stably transfected human 36 melanoma cell line expressing EGFP under the control of a 2.2-kb fragment derived from the 37 tyrosinase gene was generated. Spontaneous induction of the tyrosinase prom...
Continuous exposure to ultraviolet B (UVB) can cause photodamage of the skin. This photodamage ca... more Continuous exposure to ultraviolet B (UVB) can cause photodamage of the skin. This photodamage can be inhibited by the overexpression of the non-coding RNA, nc886, via the protein kinase RNA-activated (PKR) pathway. The study aims to identify how UVB inhibits nc886 expression, and it also seeks to determine whether substances that can control nc886 expression can influence UV-induced inflammation, and the mechanisms involved. The results suggest that UVB irradiation accelerates the methylation of the nc886 gene, therefore, reducing its expression. This induces the activation of the PKR, which accelerates the expression of metalloproteinase-9 (MMP-9) and cyclooxygenase (COX-2), and the production of MMP-9, prostaglandin-endoperoxide synthase (PGE2), and certain pro-inflammatory cytokines, specifically interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Conversely, in a model of nc886 overexpression, the expression and production of those inflammatory factors are inhibited. In ...
Evidence-Based Complementary and Alternative Medicine, 2019
Mentha suaveolens is an aromatic herb that has a wide range of biological activities, including a... more Mentha suaveolens is an aromatic herb that has a wide range of biological activities, including antimicrobial, antifungal, anti-inflammatory, and hepatoprotective properties. Although there are a few reports on the antioxidant property of M. suaveolens, its cytoprotective activity against oxidative stress has not been reported yet. The objective of this study was to determine the protective activity of M. suaveolens aqueous extract (MSAE) against hydrogen peroxide- (H2O2-) induced oxidative stress and apoptosis in human keratinocyte HaCaT cells. MSAE pretreatment decreased H2O2-induced cytotoxicity and suppressed H2O2-induced intracellular ROS generation. Furthermore, MSAE suppressed expression levels of H2O2-induced apoptotic genes such as cleaved caspase-3, caspase-9, and cleaved poly (ADP-ribose) polymerase (PARP). Pretreatment with MSAE induced expression of phase II enzyme such as HO-1 through translocation of NF-E2-related factor (Nrf2) upon H2O2 exposure. These results reveal...
Evidence-based complementary and alternative medicine : eCAM, 2018
Thermal skin aging refers to skin aging induced by heat shock treatment. Apple mint ( Ehrh.) has ... more Thermal skin aging refers to skin aging induced by heat shock treatment. Apple mint ( Ehrh.) has been used as a folk medicine to treat various diseases. However, the activity of apple mint in thermal skin aging has yet to be investigated. In this study, we conducted various biological assays to demonstrate the anti-thermal skin aging activity of extracts of apple mint leaves (ALE). As a result, ALE showed significant antioxidant activities and inhibited the production of reactive oxygen species (ROS), matrix metalloproteinases (MMPs), and interleukin-8 (IL-8) as well as suppressed mitogen-activated proteins kinases (MAPKs) such as extracellular signal regulated kinases (ERK), c-Jun N terminal kinases (JNK), and p38 MAPK triggered by heat shock treatment in human dermal fibroblasts (HDFs). Consequently, ALE could be used as attractive cosmetic materials with anti-thermal skin aging activity.
Skin circadian clock system responds to daily changes, thereby regulating skin functions. Exposur... more Skin circadian clock system responds to daily changes, thereby regulating skin functions. Exposure of the skin to UV irradiation induces the expression of matrix metalloproteinase-1 (MMP-1) and causes DNA damage. It has been reported both DNA repair and DNA replication are regulated by the circadian clock in mouse skin. However, the molecular link between circadian clock and MMP-1 has little been investigated. We found PERIOD protein, a morning clock component, represses the expression of MMP-1 in human keratinocytes by using a PER-knockdown strategy. Treatment with siPer3 alleviated the suppression of MMP-1 expression induced by forskolin. Results revealed PER3 suppresses the expression of MMP-1 via cAMP signaling pathway. Additionally, we screened for an activator of PER that could repress the expression of MMP-1 using HaCaT cell line containing promoter-luciferase reporter gene. Results showed extract (LCE) increased promoter activity. LCE inhibited the expression of MMP-1 and it...
Ginseng leaves contain high saponin composition and content, but are used less often than the roo... more Ginseng leaves contain high saponin composition and content, but are used less often than the root part. To develop a use for the leaves that exploits their properties, we studied ginseng leaves as the raw material of anti-aging cosmetics. This study highlights an assessment of the cellular factivity and clinical efficacy of ginseng leaf extract, providing necessary information relevant to the development of new cosmetic products. Panax ginseng leaf purified extracts (PGLE) were shown to have high contents of Rb3 and Rb2. Rb3, the major chemical components of PGLE, promoted collagen synthesis though the activation of transforming growth factor-β (TGF-β) in human skin fibroblast cells. In addition, the possibility of PGLE as an anti-skin-aging agent has also been clinically validated. Our analysis of the crow’s feet wrinkle showed that there was a decrease in the depth of deep furrows in the region of interest (RI) treated with PGLE lotion over an eight-week period. Based on these re...
The accumulation of free radicals and advanced glycation end products (AGEs) in the skin plays a ... more The accumulation of free radicals and advanced glycation end products (AGEs) in the skin plays a very important role in skin aging. Both are known to interact with each other. Therefore, natural compounds or extracts that possess both antioxidant and antiglycation activities might have great antiageing potential. Akebia quinata fruit extract (AQFE) has been used to treat urinary tract inflammatory disease in traditional Korean and Chinese medicines. In the present study, AQFE was demonstrated to possess antioxidant and antiglycation activity. AQFE protects human dermal fibroblasts (HDFs) from oxidative stress and inhibits cellular senescence induced by oxidative stress. We also found that AQFE inhibits glycation reaction between BSA and glucose. The antiglycation activity of AQFE was dose-dependent. In addition, the antiglycation activity of AQFE was confirmed in a human skin explant model. AQFE reduced CML expression and stimulated fibrillin-1 expression in comparison to the methyg...
International journal of molecular sciences, Jan 20, 2014
The phenolic compound phloretin is a prominent member of the chemical class of dihydrochalcones. ... more The phenolic compound phloretin is a prominent member of the chemical class of dihydrochalcones. Phloretin is specifically found in apple and apple juice and known for its biological properties. We were particularly interested in its potential dermo-cosmetic applications. However, practical limitations of phloretin do exist due to its poor water-solubility. Phloretin was sulfonated with sulfuric acid (98%, wt) and mixed with saturated salt water to produce phloretin 3',3-disulfonate in order to increase its water-solubility. Here we reported the photoprotective effect of phloretin 3',3-disulfonate (PS), a new semi-synthetic derivative of phloretin. Results showed that PS attenuated cyclobutane pyrimidine dimer (CPDs) formation, glutathione (GSH) depletion and apoptosis induced by ultraviolet B (UVB). The photoprotective effect of PS is tightly correlated to the enhancement of nucleotide excision repair (NER) gene expression. Furthemore, PS had inhibitory effects on UVB-induc...
This study investigated the effect of 7,8-dihydroxyflavone (DHF) on the expression and activity o... more This study investigated the effect of 7,8-dihydroxyflavone (DHF) on the expression and activity of heme oxygenase-1 (HO-1), an enzyme with potent antioxidant properties, as well as the molecular mechanisms involved. DHF markedly upregulated HO-1 mRNA and protein expression in human keratinocytes (HaCaT cells), resulting in increased HO-1 activity. DHF also increased the protein level of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates HO-1 expression by binding to the antioxidant response element (ARE) within the HO-1 gene promoter, in a time-dependent manner. Moreover, DHF decreased the expression of Kelch-like ECH-associated protein 1, a repressor of Nrf2 activity, and induced the translocation of Nrf2 from the cytosol into the nucleus, thereby allowing its association with the ARE site. DHF activated extracellular-regulated kinase (ERK) and protein kinase B (PKB, Akt) in keratinocytes, while the ERK and Akt inhibitors attenuated DHF-enhance...
Senescent fibroblasts progressively deteriorate the functional properties of skin tissue. Senesce... more Senescent fibroblasts progressively deteriorate the functional properties of skin tissue. Senescent cells secrete senescence-associated secretory phenotype (SASP) factor, which causes the aging of surrounding non-senescent cells and accelerates aging in the individuals. Recent findings suggested the senomorphic targeting of the SASP regulation as a new generation of effective therapeutics. We investigated whether Isatis tinctoria L. leaf extract (ITE) inhibited senescence biomarkers p53, p21CDKN1A, and p16INK4A gene expression, and SASP secretions by inhibiting cellular senescence in the replicative senescent human dermal fibroblast (RS-HDF). ITE has been demonstrated to inhibit the secretion of SASP factors in several senomorphic types by regulating the MAPK/NF-κB pathway via its inhibitory effect on mTOR. ITE suppressed the inflammatory response by inhibiting mTOR, MAPK, and IκBα phosphorylation, and blocking the nuclear translocation of NF-κB. In addition, we observed that autoph...
Inflammation is increasingly recognized as a critical mediator of angiogenesis, and unregulated a... more Inflammation is increasingly recognized as a critical mediator of angiogenesis, and unregulated angiogenic responses often involve human diseases. The importance of regulating angiogenesis in inflammatory diseases has been demonstrated through some successful cases of anti-angiogenesis therapies in related diseases, including arthritis, but it has been reported that some synthetic types of antiangiogenic drugs have potential side effects. In recent years, the importance of finding alternative strategies for regulating angiogenesis has begun to attract the attention of researchers. Therefore, identification of natural ingredients used to prevent or treat angiogenesis-related diseases will play a greater role. Isookanin is a phenolic flavonoid presented in Bidens extract, and it has been reported that isookanin possesses some biological properties, including antioxidative and anti-inflammatory effects, anti-diabetic properties, and an ability to inhibit α-amylase. However, its antiang...
Inflammaging refers to chronic, lowgrade inflammation that contributes to the aging process. A gr... more Inflammaging refers to chronic, lowgrade inflammation that contributes to the aging process. A growing number of references specify that aging is driven by proinflammatory cytokines produced by the innate immune system which involve the inflammasome and Nfkb pathways. These two pathways are interconnected and share a common inducer, the double-stranded RNA-dependent protein kinase PKR. Recently, we showed that inflammation is controlled by an epigenetic process involving PKR and the long noncoding RNA lnc886. Lnc886 regulates inflammation by the direct inhibition of PKR phosphorylation. Although the literature suggests that excessive inflammasome activity leads to inflammaging in age-related pathologies, this has not been not demonstrated for skin aging. The present paper effectively illustrates that along with aging and concomitantly with decreased expression of lnc886 (the PKR inhibitor), the inflammasome is activated. Using several innovative inflammasome models, we demonstrate t...
27 For screening of skin-whitening ingredients that modulate inhibition of melanogenesis, 28 tyro... more 27 For screening of skin-whitening ingredients that modulate inhibition of melanogenesis, 28 tyrosinase promoter-based assay using a 3D spheroid culture technique is a beneficial tool to 29 improve the accuracy of raw material screening in cosmetics through mimicking of the in 30 vivo microenvironment. Although the advantages of high-throughput screening (HTS) are 31 widely known, there has been little focus on specific cell-based promoter assays for HTS in 32 identifying skin-whitening ingredients that inhibit accumulation of melanin. The aim of this 33 study was therefore to develop a large-scale compatible assay through pTyr-EGFP, an 34 enhanced green fluorescent protein (EGFP)-based tyrosinase-specific promoter, to seek 35 potential melanogenesis inhibitors for cosmetic use. Herein, a stably transfected human 36 melanoma cell line expressing EGFP under the control of a 2.2-kb fragment derived from the 37 tyrosinase gene was generated. Spontaneous induction of the tyrosinase prom...
Continuous exposure to ultraviolet B (UVB) can cause photodamage of the skin. This photodamage ca... more Continuous exposure to ultraviolet B (UVB) can cause photodamage of the skin. This photodamage can be inhibited by the overexpression of the non-coding RNA, nc886, via the protein kinase RNA-activated (PKR) pathway. The study aims to identify how UVB inhibits nc886 expression, and it also seeks to determine whether substances that can control nc886 expression can influence UV-induced inflammation, and the mechanisms involved. The results suggest that UVB irradiation accelerates the methylation of the nc886 gene, therefore, reducing its expression. This induces the activation of the PKR, which accelerates the expression of metalloproteinase-9 (MMP-9) and cyclooxygenase (COX-2), and the production of MMP-9, prostaglandin-endoperoxide synthase (PGE2), and certain pro-inflammatory cytokines, specifically interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Conversely, in a model of nc886 overexpression, the expression and production of those inflammatory factors are inhibited. In ...
Evidence-Based Complementary and Alternative Medicine, 2019
Mentha suaveolens is an aromatic herb that has a wide range of biological activities, including a... more Mentha suaveolens is an aromatic herb that has a wide range of biological activities, including antimicrobial, antifungal, anti-inflammatory, and hepatoprotective properties. Although there are a few reports on the antioxidant property of M. suaveolens, its cytoprotective activity against oxidative stress has not been reported yet. The objective of this study was to determine the protective activity of M. suaveolens aqueous extract (MSAE) against hydrogen peroxide- (H2O2-) induced oxidative stress and apoptosis in human keratinocyte HaCaT cells. MSAE pretreatment decreased H2O2-induced cytotoxicity and suppressed H2O2-induced intracellular ROS generation. Furthermore, MSAE suppressed expression levels of H2O2-induced apoptotic genes such as cleaved caspase-3, caspase-9, and cleaved poly (ADP-ribose) polymerase (PARP). Pretreatment with MSAE induced expression of phase II enzyme such as HO-1 through translocation of NF-E2-related factor (Nrf2) upon H2O2 exposure. These results reveal...
Evidence-based complementary and alternative medicine : eCAM, 2018
Thermal skin aging refers to skin aging induced by heat shock treatment. Apple mint ( Ehrh.) has ... more Thermal skin aging refers to skin aging induced by heat shock treatment. Apple mint ( Ehrh.) has been used as a folk medicine to treat various diseases. However, the activity of apple mint in thermal skin aging has yet to be investigated. In this study, we conducted various biological assays to demonstrate the anti-thermal skin aging activity of extracts of apple mint leaves (ALE). As a result, ALE showed significant antioxidant activities and inhibited the production of reactive oxygen species (ROS), matrix metalloproteinases (MMPs), and interleukin-8 (IL-8) as well as suppressed mitogen-activated proteins kinases (MAPKs) such as extracellular signal regulated kinases (ERK), c-Jun N terminal kinases (JNK), and p38 MAPK triggered by heat shock treatment in human dermal fibroblasts (HDFs). Consequently, ALE could be used as attractive cosmetic materials with anti-thermal skin aging activity.
Skin circadian clock system responds to daily changes, thereby regulating skin functions. Exposur... more Skin circadian clock system responds to daily changes, thereby regulating skin functions. Exposure of the skin to UV irradiation induces the expression of matrix metalloproteinase-1 (MMP-1) and causes DNA damage. It has been reported both DNA repair and DNA replication are regulated by the circadian clock in mouse skin. However, the molecular link between circadian clock and MMP-1 has little been investigated. We found PERIOD protein, a morning clock component, represses the expression of MMP-1 in human keratinocytes by using a PER-knockdown strategy. Treatment with siPer3 alleviated the suppression of MMP-1 expression induced by forskolin. Results revealed PER3 suppresses the expression of MMP-1 via cAMP signaling pathway. Additionally, we screened for an activator of PER that could repress the expression of MMP-1 using HaCaT cell line containing promoter-luciferase reporter gene. Results showed extract (LCE) increased promoter activity. LCE inhibited the expression of MMP-1 and it...
Ginseng leaves contain high saponin composition and content, but are used less often than the roo... more Ginseng leaves contain high saponin composition and content, but are used less often than the root part. To develop a use for the leaves that exploits their properties, we studied ginseng leaves as the raw material of anti-aging cosmetics. This study highlights an assessment of the cellular factivity and clinical efficacy of ginseng leaf extract, providing necessary information relevant to the development of new cosmetic products. Panax ginseng leaf purified extracts (PGLE) were shown to have high contents of Rb3 and Rb2. Rb3, the major chemical components of PGLE, promoted collagen synthesis though the activation of transforming growth factor-β (TGF-β) in human skin fibroblast cells. In addition, the possibility of PGLE as an anti-skin-aging agent has also been clinically validated. Our analysis of the crow’s feet wrinkle showed that there was a decrease in the depth of deep furrows in the region of interest (RI) treated with PGLE lotion over an eight-week period. Based on these re...
The accumulation of free radicals and advanced glycation end products (AGEs) in the skin plays a ... more The accumulation of free radicals and advanced glycation end products (AGEs) in the skin plays a very important role in skin aging. Both are known to interact with each other. Therefore, natural compounds or extracts that possess both antioxidant and antiglycation activities might have great antiageing potential. Akebia quinata fruit extract (AQFE) has been used to treat urinary tract inflammatory disease in traditional Korean and Chinese medicines. In the present study, AQFE was demonstrated to possess antioxidant and antiglycation activity. AQFE protects human dermal fibroblasts (HDFs) from oxidative stress and inhibits cellular senescence induced by oxidative stress. We also found that AQFE inhibits glycation reaction between BSA and glucose. The antiglycation activity of AQFE was dose-dependent. In addition, the antiglycation activity of AQFE was confirmed in a human skin explant model. AQFE reduced CML expression and stimulated fibrillin-1 expression in comparison to the methyg...
International journal of molecular sciences, Jan 20, 2014
The phenolic compound phloretin is a prominent member of the chemical class of dihydrochalcones. ... more The phenolic compound phloretin is a prominent member of the chemical class of dihydrochalcones. Phloretin is specifically found in apple and apple juice and known for its biological properties. We were particularly interested in its potential dermo-cosmetic applications. However, practical limitations of phloretin do exist due to its poor water-solubility. Phloretin was sulfonated with sulfuric acid (98%, wt) and mixed with saturated salt water to produce phloretin 3',3-disulfonate in order to increase its water-solubility. Here we reported the photoprotective effect of phloretin 3',3-disulfonate (PS), a new semi-synthetic derivative of phloretin. Results showed that PS attenuated cyclobutane pyrimidine dimer (CPDs) formation, glutathione (GSH) depletion and apoptosis induced by ultraviolet B (UVB). The photoprotective effect of PS is tightly correlated to the enhancement of nucleotide excision repair (NER) gene expression. Furthemore, PS had inhibitory effects on UVB-induc...
This study investigated the effect of 7,8-dihydroxyflavone (DHF) on the expression and activity o... more This study investigated the effect of 7,8-dihydroxyflavone (DHF) on the expression and activity of heme oxygenase-1 (HO-1), an enzyme with potent antioxidant properties, as well as the molecular mechanisms involved. DHF markedly upregulated HO-1 mRNA and protein expression in human keratinocytes (HaCaT cells), resulting in increased HO-1 activity. DHF also increased the protein level of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates HO-1 expression by binding to the antioxidant response element (ARE) within the HO-1 gene promoter, in a time-dependent manner. Moreover, DHF decreased the expression of Kelch-like ECH-associated protein 1, a repressor of Nrf2 activity, and induced the translocation of Nrf2 from the cytosol into the nucleus, thereby allowing its association with the ARE site. DHF activated extracellular-regulated kinase (ERK) and protein kinase B (PKB, Akt) in keratinocytes, while the ERK and Akt inhibitors attenuated DHF-enhance...
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