Dual role of enhancer of zeste homolog 2 in the regulation of ultraviolet radiation-induced matrix metalloproteinase-1 and type I procollagen expression in human dermal fibroblasts.

Abnormalities in the extracellular matrix (ECM) caused by ultraviolet (UV) radiation are mediated by epigenetic mechanisms. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is implicated in inflammation, immune regulation, and senescence. However, its role in controlling UV-induced ECM alterations in the skin remains elusive. Here, we investigated the role of EZH2 in UV-induced expression of matrix metalloproteinase (MMP)-1 and type I procollagen. We found that UV induced EZH2 expression in human skin in vivo and in human dermal fibroblasts (HDFs). EZH2 knockdown reduced the expression and promoter activity of MMP-1 and increased those of type I procollagen, whereas EZH2 overexpression had the opposite effects. Mechanistically, EZH2 increased NF-κB activity, and p65 and p50 expression and promoter activity. Intriguingly, chromatin immunoprecipitation assays revealed that the EZH2/p65/p50 complex was recruited and bound to the MMP-1 promoter after UV irradiation, independent of its histone methyltransferase activity. In contrast, EZH2-induced DNA methyltransferase 1 (DNMT1) formed a complex with EZH2 and enhanced the enrichment of H3K27me3 on the COL1A2 promoter following UV irradiation. These findings indicate that EZH2 plays a dual role in regulating MMP-1 and type I procollagen expression and improve our understanding of how this epigenetic mechanism contributes to UV-induced skin responses and photoaging. This study shows that inhibiting EZH2 is a potential anti-aging strategy for preventing UV-induced skin aging by reducing MMP-1 expression and inducing type I procollagen expression.

Modified Atmosphere Packaging and 1-Methylcyclopropene Treatments Maintain the Fruit Quality of 'Wonmi' Persimmons during Export Simulation.

Persimmons are one of the most important export fruits in South Korea, where several tons are exported across the globe each year. In this study, the quality attributes of 'Wonmi' persimmon fruits were evaluated during an export simulation at 0 °C, 10 °C, and 24 °C with a combination of 1-Methylcyclopropene (1-MCP) and modified atmosphere packaging (MAP) treatments. The relative humidity during the export simulation was greater at room temperature (75-92%) and 0 °C (85% to 93%) than at 10 °C (42% to 60%). The results show that the application of 1-MCP and MAP treatments during the export simulation were effective in delaying the ripening of 'Wonmi' persimmons by reducing respiration and ethylene production. The suppressed expression of ethylene synthesis genes and cell wall modification genes reduced the ethylene production and maintain the fruit firmness, respectively. In addition, 1-MCP and MAP treatments were effective in maintaining SSC and color of 'Wonmi' persimmon fruits during the export simulation. Thus, by adopting these treatments, the overall quality of persimmon exports from South Korea can significantly improve.

Field Application of a Vis/NIR Hyperspectral Imaging System for Nondestructive Evaluation of Physicochemical Properties in 'Madoka' Peaches.

Extensive research has been performed on the in-field nondestructive evaluation (NDE) of the physicochemical properties of 'Madoka' peaches, such as chromaticity (a*), soluble solids content (SSC), firmness, and titratable acidity (TA) content. To accomplish this, a snapshot-based hyperspectral imaging (HSI) approach for filed application was conducted in the visible and near-infrared (Vis/NIR) region. The hyperspectral images of 'Madoka' samples were captured and combined with commercial HSI analysis software, and then the physicochemical properties of the 'Madoka' samples were predicted. To verify the performance of the field-based HSI application, a lab-based HSI application was also conducted, and their coefficient of determination values (R2) were compared. Finally, pixel-based chemical images were produced to interpret the dynamic changes of the physicochemical properties in 'Madoka' peach. Consequently, the a* values and SSC content shows statistically significant R2 values (0.84). On the other hand, the firmness and TA content shows relatively lower accuracy (R2 = 0.6 to 0.7). Then, the resultant chemical images of the a* values and SSC content were created and could represent their different levels using grey scale gradation. This indicates that the HSI system with integrated HSI software used in this work has promising potential as an in-field NDE for analyzing the physicochemical properties in 'Madoka' peaches.

Histone deacetylase 4 reverses cellular senescence via DDIT4 in dermal fibroblasts.

Histone deacetylases (HDACs) remove acetyl groups from lysine chains on histones and other proteins and play a crucial role in epigenetic regulation and aging. Previously, we demonstrated that HDAC4 is consistently downregulated in aged and ultraviolet (UV)-irradiated human skin in vivo. Cellular senescence is a permanent cell cycle arrest induced by various stressors. To elucidate the potential role of HDAC4 in the regulation of cellular senescence and skin aging, we established oxidative stress- and UV-induced cellular senescence models using primary human dermal fibroblasts (HDFs). RNA sequencing after overexpression or knockdown of HDAC4 in primary HDFs identified candidate molecular targets of HDAC4. Integrative analyses of our current and public mRNA expression profiles identified DNA damage-inducible transcript 4 (DDIT4) as a critical senescence-associated factor regulated by HDAC4. Indeed, DDIT4 and HDAC4 expressions were downregulated during oxidative stress- and UV-induced senescence. HDAC4 overexpression rescued the senescence-induced decrease in DDIT4 and senescence phenotype, which were prevented by DDIT4 knockdown. In addition, DDIT4 overexpression reversed changes in senescence-associated secretory phenotypes and aging-related genes, suggesting that DDIT4 mediates the reversal of cellular senescence via HDAC4. Collectively, our results identify DDIT4 as a promising target regulated by HDAC4 associated with cellular senescence and epigenetic skin aging.

Histone Deacetylase 1 Reduces Lipogenesis by Suppressing SREBP1 Transcription in Human Sebocyte Cell Line SZ95.

Proper regulation of sebum production is important for maintaining skin homeostasis in humans. However, little is known about the role of epigenetic regulation in sebocyte lipogenesis. We investigated histone acetylation changes and their role in key lipogenic gene regulation during sebocyte lipogenesis using the human sebaceous gland cell line SZ95. Sebocyte lipogenesis is associated with a significant increase in histone acetylation. Treatment with anacardic acid (AA), a p300 histone acetyltransferase inhibitor, significantly decreased the lipid droplet number and the expression of key lipogenic genes, including sterol regulatory-binding protein 1 (SREBP1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). In contrast, treatment with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, increased the expression of these genes. Global HDAC enzyme activity was decreased, and HDAC1 and HDAC2 expression was downregulated during sebaceous lipogenesis. Interestingly, HDAC1 knockdown increased lipogenesis through SREBP1 induction, whereas HDAC1 overexpression decreased lipogenesis and significantly suppressed SREBP1 promoter activity. HDAC1 and SREBP1 levels were inversely correlated in human skin sebaceous glands as demonstrated in immunofluorescence images. In conclusion, HDAC1 plays a critical role in reducing SREBP1 transcription, leading to decreased sebaceous lipogenesis. Therefore, HDAC1 activation could be an effective therapeutic strategy for skin diseases related to excessive sebum production.

Increased Histone Acetylation and Decreased Expression of Specific Histone Deacetylases in Ultraviolet-Irradiated and Intrinsically Aged Human Skin In Vivo.

Histone deacetylases (HDACs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins and play a crucial role in epigenetic regulation. Previously, we showed that histone acetylation is implicated in ultraviolet (UV)-induced inflammation and matrix impairment. To elucidate the histone acetylation status and specific HDACs involved in skin aging, we examined the changes in histone acetylation, global HDAC activity, and the expression of HDACs and sirtuins (SIRTs) in intrinsically aged and photoaged human skin as well as in UV-irradiated human skin in vivo. Following acute UV irradiation, the acetylated histone H3 (AcH3) level was increased, but HDAC activity and the expression levels of HDAC4, HDAC11, and SIRT4 were significantly decreased. In intrinsically aged skin, AcH3 levels were increased, but HDAC activity and the expression levels of HDAC4, HDAC5, HDAC10, HDAC11, SIRT6, and SIRT7 were significantly decreased. However, histone acetylation and HDAC expression in photoaged skin were not significantly different from those in intrinsically aged skin. Collectively, HDAC4 and HDAC11 were decreased in both UV-irradiated and intrinsically aged skin, suggesting that they may play a universal role in increased histone acetylation associated with skin aging.

Ultraviolet irradiation-induced inhibition of histone deacetylase 4 increases the expression of matrix metalloproteinase-1 but decreases that of type I procollagen via activating JNK in human dermal fibroblasts.

BACKGROUND: Ultraviolet (UV) irradiation is the main contributing factor for skin aging. UV irradiation induces epigenetic changes in skin. It increases the activity of histone acetylases (HATs) but decreases that of histone deacetylases (HDACs). OBJECTIVE: We aimed to investigate alterations in all classes of HDACs and sirtuins (SIRTs) in response to UV irradiation, and determine the HDACs regulating the expressions of matrix metalloproteinase 1 (MMP-1) and type I procollagen. METHODS: Primary human dermal fibroblasts were UV irradiated. HDAC4 was knocked-down or overexpressed to investigate its effect on the expression of MMP-1 and type I procollagen. The mRNA and protein levels were analyzed by quantitative real-time polymerase chain reaction and western blotting. RESULTS: Among 11 HDACs and 7 SIRTs, we found that the expression of HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC11, SIRT2, and SIRT3 were significantly and consistently reduced by UV at both mRNA and protein levels. Among these, the reduction of HDAC4 was responsible for the basal and UV-induced increase in the expression of MMP-1 and decrease in that of type I procollagen. Furthermore, the reduced HDAC4 could activate c-Jun N-terminal kinase (JNK), resulting in an increase in MMP-1 and decrease in type I procollagen. CONCLUSIONS: UV treatment decreases the expression of HDACs and SIRTs in dermal fibroblasts; in particular, the UV-induced reduction in the expression of HDAC4 might play an important role in regulating the expression of MMP-1 and type I procollagen.

UV increases skin-derived 1α,25-dihydroxyvitamin D3 production, leading to MMP-1 expression by altering the balance of vitamin D and cholesterol synthesis from 7-dehydrocholesterol.

The skin is a unique site in the human body that has the capacity to synthesize the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), from 7-dehydrocholesterol (7DHC) upon UV irradiation. Keratinocytes express both 25-hydroxylase (CYP27A1 and CYP2R1) and 1α-hydroxylase (CYP27B1), critical enzymes involved in active vitamin D synthesis. Here, we investigated the effect of skin-derived 1α,25(OH)2D3, synthesized purely within the keratinocytes, on MMP-1 expression. Treatment of human epidermal keratinocytes with 1α,25(OH)2D3, but not 7DHC or 25OHD3, significantly increased MMP-1 expression. UV irradiation increases 1α,25(OH)2D3 levels, and ketoconazole inhibits UV-induced production of 1α,25(OH)2D3. Upregulation of MMP-1 by UV was reversed by inhibition of 1α,25(OH)2D3 synthesis using ketoconazole or CYP27B1 siRNA. In keratinocytes, 7DHC is a substrate for both cholesterol and 1α,25(OH)2D3 synthesis. We demonstrated that UV irradiation leads to decreased expression of DHCR7 (7-dehydrocholesterol reductase), the enzyme that converts 7DHC to cholesterol. Inhibition of DHCR7 with its inhibitor BM15766 decreased cholesterol synthesis and increased UV-induced MMP-1 expression, which was attenuated by ketoconazole. These findings suggest that UV-induced reduction of DHCR7 leads to a decrease in cholesterol synthesis, thereby increasing 7DHC availability for 1α,25(OH)2D3 production, which enhances MMP-1 expression. Finally, UV irradiation in human skin in vivo significantly increased CYP27B1 mRNA and decreased DHCR7 mRNA expression. Taken together, we demonstrate here that skin-derived 1α,25(OH)2D3 significantly increases MMP-1 expression in human keratinocytes, a previously unappreciated function of 1α,25(OH)2D3. Moreover, UV irradiation upregulates the enzyme CYP27B1, which leads to 1α,25(OH)2D3 synthesis, but downregulates the cholesterol-producing enzyme DHCR7, both of which collectively lead to increased MMP-1 expression in human keratinocytes. This pathway may be exploited to develop a novel cutaneous anti-aging agent that blocks local cutaneous 1α,25(OH)2D3 synthesis.

UV-induced DNA methyltransferase 1 promotes hypermethylation of tissue inhibitor of metalloproteinase 2 in the human skin.

BACKGROUND: Ultraviolet (UV) radiation has been reported to influence epigenetic regulation by affecting the expression of genome regulators such as DNA methyltransferase 1 (DNMT1). DNMT1 is a "gene silencer," that is responsible for the maintenance of DNA methylation and contribution to de novo methylation. Implications of DNMT1's involvement in the expression of UV-induced proteins have been previously reported. OBJECTIVE: To investigate for changes in DNA methylation-associated gene expressions by UV and to analyze the role of DNA methylation in the suppression of TIMP2 in UV-irradiated human skin. METHODS: The expression of DNA methylation-associated proteins and TIMP2 were analyzed in UV-irradiated human skin in vivo and in human dermal fibroblasts in vitro. To investigate the relationship between DNMT1 and TIMP2, we assessed the effect of DNMT1 knockdown, inhibition and overexpression on TIMP2 levels in human dermal fibroblasts. Lastly, methylation-specific PCR was used to confirm increased DNA methylation in TIMP2 promoter in response to UV. RESULTS: DNMT1 expression significantly increased whereas TIMP2 expression decreased in UV-irradiated human skin in vivo and in vitro. Downregulation of DNMT1 by knockdown or inhibition resulted in increased TIMP2 expression, whereas the overexpression of DNMT1 resulted in decreased TIMP2 expression. Lastly, methylation-specific PCR confirmed increased methylation on the CpG island residing in TIMP2 promoter in UV-irradiated human dermal fibroblasts. CONCLUSION: These findings suggest that UV-induced expression of DNMT1 may be responsible for mediating DNA hypermethylation in TIMP2, and thus, silencing its expression, in UV-exposed human skin.

Inhibition of DNA Methylation in the COL1A2 Promoter by Anacardic Acid Prevents UV-Induced Decrease of Type I Procollagen Expression.

UV radiation decreases type I procollagen production mainly by inhibiting the transforming growth factor-ß/Smad signaling pathway. Because further epigenetic regulatory mechanisms are unclear, we investigated the roles of DNA methylation and histone acetylation in UV-induced regulation of COL1A2 transcription in human dermal fibroblasts. Anacardic acid, a p300 histone acetyltransferase inhibitor, rescued the UV-induced decrease of type I procollagen expression in human dermal fibroblasts. Although UV irradiation induced global histone acetylation, it reduced the local recruitment of histone H3 acetylation as well as p300, and Smad2/3 to the p300 binding site (-1406/-1393), in the COL1A2 promoter as shown by chromatin immunoprecipitation. This effect was reversed by anacardic acid treatment. In contrast, pyrosequencing analysis showed that UV irradiation induced DNA methylation in the same region of the COL1A2 promoter, which was reversed by anacardic acid and a DNA methyltransferase inhibitor (5-AZA-2'-deoxycytidine). Inhibition of UV-induced DNA methylation led to an increase of UV-induced histone acetylation in the COL1A2 promoter and increased the recruitment of transcription factors, leading to up-regulation of type I collagen after UV irradiation. Collectively, our findings indicate that the epigenetic crosstalk between DNA methylation and histone acetylation plays a crucial role in COL1A2 transcription induced by UV irradiation.

Activation of Peroxisome Proliferator-Activated Receptor Alpha Improves Aged and UV-Irradiated Skin by Catalase Induction.

Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear hormone receptor involved in the transcriptional regulation of lipid metabolism, fatty acid oxidation, and glucose homeostasis. Its activation stimulates antioxidant enzymes such as catalase, whose expression is decreased in aged human skin. Here we investigated the expression of PPARα in aged and ultraviolet (UV)-irradiated skin, and whether PPARα activation can modulate expressions of matrix metalloproteinase (MMP)-1 and procollagen through catalase regulation. We found that PPARα mRNA level was significantly decreased in intrinsically aged and photoaged human skin as well as in UV-irradiated skin. A PPARα activator, Wy14643, inhibited UV-induced increase of MMP-1 and decrease of procollagen expression and caused marked increase in catalase expression. Furthermore, production of reactive oxygen species (ROS) was suppressed by Wy14643 in UV-irradiated and aged dermal fibroblasts, suggesting that the PPARα activation-induced upregulation of catalase leads to scavenging of ROS produced due to UV irradiation or aging. PPARα knockdown decreased catalase expression and abolished the beneficial effects of Wy14643. Topical application of Wy14643 on hairless mice restored catalase activity and prevented MMP-13 and inflammatory responses in skin. Our findings indicate that PPARα activation triggers catalase expression and ROS scavenging, thereby protecting skin from UV-induced damage and intrinsic aging.

Pleiotrophin is downregulated in human keloids.

Keloid is an abnormal hyperproliferative scarring process with involvement of complex genetic and triggering environmental factors. Previously published dysregulated gene expression profile of keloids includes genes involved in tumor formation. Pleiotrophin (PTN) is a secreted, heparin-binding growth factor which is involved in various biological functions such as cell growth, differentiation, and tumor progression. Although PTN expression was reported to be increased in hypertrophic scars, there is no study on PTN expression in keloids, and previous microarray results are controversial. To clarify differential expression of PTN in keloids, we investigated the expression of PTN and its interacting molecules in keloid and control fibroblasts, and performed immunohistochemical staining of PTN using tissue arrays. The expressions of PTN, its upstream regulator platelet-derived growth factor subunit B (PDGF-B) and corresponding PDGF receptors were significantly downregulated in keloid fibroblasts compared to normal human fibroblasts, and the decreased PTN protein expression was confirmed by immunohistochemistry as well as Western blot. Moreover, functional downstream receptor protein tyrosine phosphatase ß/ζ was significantly upregulated in keloid fibroblasts, supporting overall downregulation of PTN signaling pathway. The lowered PTN expression in keloids suggests a different pathomechanism from that of hypertrophic scars.

Supplementating with dietary astaxanthin combined with collagen hydrolysate improves facial elasticity and decreases matrix metalloproteinase-1 and -12 expression: a comparative study with placebo.

Photoaging accounts for most age-related changes in skin appearance. It has been suggested that both astaxanthin, a potent antioxidant, and collagen hydrolysate can be used as antiaging modalities in photoaged skin. However, there is no clinical study using astaxanthin combined with collagen hydrolysate. We investigated the effects of using a combination of dietary astaxanthin and collagen hydrolysate supplementation on moderately photoaged skin in humans. A total of 44 healthy subjects were recruited and treated with astaxanthin (2 mg/day) combined with collagen hydrolysate (3 g/day) or placebos, which were identical in appearance and taste to the active supplementation for 12 weeks. The elasticity and hydration properties of facial skin were evaluated using noninvasive objective devices. In addition, we also evaluated the expression of procollagen type I, fibrillin-1, matrix metalloproteinase-1 (MMP-1) and -12, and ultraviolet (UV)-induced DNA damage in artificially UV-irradiated buttock skin before and after treatment. The supplement group showed significant improvements in skin elasticity and transepidermal water loss in photoaged facial skin after 12 weeks compared with the placebo group. In the supplement group, expression of procollagen type I mRNA increased and expression of MMP-1 and -12 mRNA decreased compared with those in the placebo group. In contrast, there was no significant difference in UV-induced DNA damage between groups. These results demonstrate that dietary astaxanthin combined with collagen hydrolysate can improve elasticity and barrier integrity in photoaged human facial skin, and such treatment is well tolerated.

Epigallocatechin-3-gallate prevents heat shock-induced MMP-1 expression by inhibiting AP-1 activity in human dermal fibroblasts.

The anti-skin aging effects of epigallocatechin-3-gallate (EGCG) have been studied extensively in vitro and in vivo models. Accumulating data suggest that EGCG possesses important antioxidant and photoprotective properties. Our previous study demonstrated that heat exposure induces cutaneous angiogenesis and inflammatory cellular infiltration, disrupts the dermal extracellular matrix by inducing matrix metalloproteinases, and alters dermal structural proteins, thereby causing premature skin aging. In the present study, we examined whether EGCG may inhibit expression of MMP-1 in heat-stimulated human dermal fibroblasts. Furthermore, we investigated the inhibitory mechanism of EGCG on heat-induced MMP-1 expression. Western blot analysis and MMP-1 promoter assay revealed that EGCG markedly inhibited heat shock-induced MMP-1 expression in human dermal fibroblasts. In addition, we found that heat shock increased AP-1 DNA binding activity, and c-Jun was found to be increased mostly by heat stimulation in a supershift assay, which were suppressed by EGCG treatment. Also, in Western blotting, EGCG significantly inhibited the heat-induced expression of AP-1 constituent proteins, c-Jun, JunB and c-Fos. These results demonstrated that EGCG has abilities to inhibit heat-induced collagenolytic MMP-1 production via interfering with AP-1 pathways. Therefore, we propose that EGCG may be a potential agent for the prevention and treatment for heat shock-induced skin aging (thermal skin aging).

Atomic hydrogen surrounded by water molecules, H(H2O)m, modulates basal and UV-induced gene expressions in human skin in vivo.

Recently, there has been much effort to find effective ingredients which can prevent or retard cutaneous skin aging after topical or systemic use. Here, we investigated the effects of the atomic hydrogen surrounded by water molecules, H(H2O)m, on acute UV-induced responses and as well as skin aging. Interestingly, we observed that H(H2O)m application to human skin prevented UV-induced erythema and DNA damage. And H(H2O)m significantly prevented UV-induced MMP-1, COX-2, IL-6 and IL-1ß mRNA expressions in human skin in vivo. We found that H(H2O)m prevented UV-induced ROS generation and inhibited UV-induced MMP-1, COX-2 and IL-6 expressions, and UV-induced JNK and c-Jun phosphorylation in HaCaT cells. Next, we investigated the effects of H(H2O)m on intrinsically aged or photoaged skin of elderly subjects. In intrinsically aged skin, H(H2O)m application significantly reduced constitutive expressions of MMP-1, IL-6, and IL-1ß mRNA. Additionally, H(H2O)m significantly increased procollagen mRNA and also decreased MMP-1 and IL-6 mRNA expressions in photoaged facial skin. These results demonstrated that local application of H(H2O)m may prevent UV-induced skin inflammation and can modulate intrinsic skin aging and photoaging processes. Therefore, we suggest that modifying the atmospheric gas environment within a room may be a new way to regulate skin functions or skin aging.

Effectiveness of lorazepam-assisted interviews in an adolescent with dissociative amnesia: A case report.

To facilitate gathering information during a psychiatric interview, some psychiatrists advocate augmenting the interview using drugs. Rather than barbiturates, benzodiazepines have been used for drug-assisted interviews. Dissociative amnesia is one of the indications for these interviews. Herein, we present the case of a 15-year-old female who was diagnosed as having dissociative amnesia because of conflicts with her friends. She was administered a lorazepam-assisted interview to aid recovery of her memories. In this case, a small dose of lorazepam was sufficient to recover her memories without any adverse effects.

Acute UV irradiation increases heparan sulfate proteoglycan levels in human skin.

Glycosaminoglycans are important structural components in the skin and exist as various proteoglycan forms, except hyaluronic acid. Heparan sulfate (HS), one of the glycosaminoglycans, is composed of repeated disaccharide units, which are glucuronic acids linked to an N-acetyl-glucosamine or its sulfated forms. To investigate acute ultraviolet (UV)-induced changes of HS and HS proteoglycans (HSPGs), changes in levels of HS and several HSPGs in male human buttock skin were examined by immunohistochemistry and real-time quantitative polymerase chain reaction (qPCR) after 2 minimal erythema doses (MED) of UV irradiation (each n = 4-7). HS staining revealed that 2 MED of UV irradiation increased its expression, and staining for perlecan, syndecan-1, syndecan-4, CD44v3, and CD44 showed that UV irradiation increased their protein levels. However, analysis by real-time qPCR showed that UV irradiation did not change mRNA levels of CD44 and agrin, and decreased perlecan and syndecan-4 mRNA levels, while increased syndecan-1 mRNA level. As HS-synthesizing or -degrading enzymes, exostosin-1 and heparanase mRNA levels were increased, but exostosin-2 was decreased by UV irradiation. UV-induced matrix metalloproteinase-1 expression was confirmed for proper experimental conditions. Acute UV irradiation increases HS and HSPG levels in human skin, but their increase may not be mediated through their transcriptional regulation.

Chronic heat treatment causes skin wrinkle formation and oxidative damage in hairless mice.

We have previously demonstrated that heat shock could induce expression of matrix metalloproteinases (MMPs) in skin cells. These results implicated that chronic heat treatment may cause skin wrinkles. Therefore, in the present study, we investigated the effects of chronic heat treatment (43 °C, 30 min, 3 times/week, 6 weeks) on wrinkle formation in skin of hairless mice. We found that repetitive heat treatment induced skin wrinkles after a period of 6 weeks in skin of hairless mice. Histologically, heat treatment resulted in increased thickness of the epidermis and dermis. And repetitive heat treatment resulted in significantly increased expression of MMP-13 protein and mRNA, but not MMP-2 and -9, in skin of hairless mice. We also demonstrated that activities of antioxidant enzymes, catalase, and superoxide dismutase (SOD), were reduced by chronic heat treatment. In addition, oxidative damage was increased in skin of mice after chronic exposure to heat shock. Taken together, our results suggested that chronic exposure of the skin to heat can cause skin wrinkling. And, increase of MMP-13, decrease of antioxidant enzymes activity, and consequent oxidative damage by chronic heat treatment may play an important role in development of skin aging in hairless mice.