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Aging is accompanied by impaired mitochondrial function and accumulation of senescent cells. Mitochondrial dysfunction contributes to senescence by increasing the levels of reactive oxygen species and compromising energy metabolism. Senescent cells secrete a senescence‐associated secretory phenotype (SASP) and stimulate chronic low‐grade inflammation, ultimately inducing inflammaging. Mitochondrial dysfunction and cellular senescence are two closely related hallmarks of aging; however, the key driver genes that link mitochondrial dysfunction and cellular senescence remain unclear. Here, we aimed to elucidate a novel role of carnitine acetyltransferase (CRAT) in the development of mitochondrial dysfunction and cellular senescence in dermal fibroblasts. Transcriptomic analysis of skin tissues from young and aged participants showed significantly decreased CRAT expression in intrinsically aged skin. CRAT downregulation in human dermal fibroblasts recapitulated mitochondrial changes in senescent cells and induced SASP secretion. Specifically, CRAT knockdown caused mitochondrial dysfunction, as indicated by increased oxidative stress, disruption of mitochondrial morphology, and a metabolic shift from oxidative phosphorylation to glycolysis. Mitochondrial damage induced the release of mitochondrial DNA into the cytosol, which activated the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) and NF‐ĸB pathways to induce SASPs. Consistently, fibroblast‐specific CRAT‐knockout mice showed increased skin aging phenotypes in vivo, including decreased cell proliferation, increased SASP expression, increased inflammation, and decreased collagen density. Our results suggest that CRAT deficiency contributes to aging by mediating mitochondrial dysfunction‐induced senescence. [ABSTRACT FROM AUTHOR]

• A natural compound harmine decreased melanin synthesis and tyrosinase expression in human MNT-1 melanoma cells and human primary melanocytes. • Melanin synthesis was reduced by inhibition of DYRK1A, a harmine target, and enhanced by knockdown of NFATC3, a potential DYRK1A target. • Harmine decreases melanin synthesis through regulation of the DYRK1A/NFATC3 pathway. Melanin plays important roles in determining human skin color and protecting human skin cells against harmful ultraviolet light. However, abnormal hyperpigmentation in some areas of the skin may become aesthetically unpleasing, resulting in the need for effective agents or methods to regulate undesirable hyperpigmentation. We investigated the effect of harmine, a natural harmala alkaloid belonging to the beta-carboline family, on melanin synthesis and further explored the signaling pathways involved in its mechanism of action. Human MNT-1 melanoma cells and human primary melanocytes were treated with harmine, chemical inhibitors, small interfering RNAs, or mammalian expression vectors. Cell viability, melanin content, and expression of various target molecules were assessed. Harmine decreased melanin synthesis and tyrosinase expression in human MNT-1 melanoma cells. Inhibition of DYRK1A, a harmine target, decreased melanin synthesis and tyrosinase expression. Further studies revealed that nuclear translocation of NFATC3, a potential DYRK1A substrate, was induced via the harmine/DYRK1A pathway and that NFATC3 knockdown increased melanin synthesis and tyrosinase expression. Suppression of melanin synthesis and tyrosinase expression via the harmine/DYRK1A pathway was significantly attenuated by NFATC3 knockdown. Furthermore, harmine also decreased melanin synthesis and tyrosinase expression through regulation of NFATC3 in human primary melanocytes. Our results indicate that harmine decreases melanin synthesis through regulation of the DYRK1A/NFATC3 pathway and suggest that the DYRK1A/NFATC3 pathway may be a potential target for the development of depigmenting agents. [ABSTRACT FROM AUTHOR]

Abstract: Background: Many extracellular stimuli, including epidermal growth factor (EGF), are known to induce MMP-1 expression. Recently, several reports have shown that ERK activity plays an important role in EGF-induced MMP-1 expression. However, EGF is also known to activate many signaling pathways in addition to the ERK pathway, but the roles of these pathways during the induction of MMP-1 by EGF are unclear. Objective: We investigated the role of JNK, p38 MAPK, and PI3K/Akt pathways in EGF-induced MMP-1 expression in human skin fibroblasts. Then, we further explored the inhibitory effect of p38 MAPK pathway on EGF-induced MMP-1 expression and studied the molecular mechanisms involved in the processes. Methods: Human skin fibroblasts were pretreated with various chemical inhibitors or small interfering RNA (siRNA) at the indicated concentrations and then treated with EGF, TNF-alpha, or IL-1beta for the indicated times. Protein and mRNA levels of various target molecules were assessed by Western blotting and quantitative real-time PCR, respectively. Results: We found that EGF-induced MMP-1 expression was positively regulated by JNK as well as ERK but negatively regulated by p38 MAPK in human skin fibroblasts. On the other hand, the PI3K/Akt pathway did not significantly affect MMP-1 induction by EGF. Then we found that the inhibition of p38 MAPK pathway specifically increased the MMP-1 expression stimulated by EGF but not by TNF-alpha or IL-1beta, indicating that the effect of p38 MAPK on MMP-1 expression may be stimulus-type specific in human skin fibroblasts. In addition, the inhibitory effect of p38 MAPK on EGF-induced MMP-1 expression was shown to be mainly mediated by p38-alpha MAPK. Our further studies showed that the inhibition of p38 MAPK but not PI3K specifically increased EGF-induced ERK and JNK activations, and that the augmentation of EGF-induced MMP-1 expression by p38 MAPK inhibition was significantly attenuated by inhibiting the activities of ERK and/or JNK. Conclusions: Our results indicate that EGF-induced MMP-1 expression is differentially regulated by the JNK, p38 MAPK, and PI3K/Akt pathways, and suggest that p38 MAPK negatively regulates EGF-induced MMP-1 expression by suppressing the activations of ERK and JNK. [Copyright &y& Elsevier]

In our previous study, we uncovered a novel mechanism in which amelioration of Hutchinson-Gilford progeria syndrome (HGPS) phenotype is mediated by mitochondrial functional recovery upon rho-associated protein kinase (ROCK) inhibition. However, it remains elusive whether this mechanism is also applied to the amelioration of normal aging cells. In this study, we used Y-27632 and fasudil as effective ROCK inhibitors, and examined their role in senescence. We found that ROCK inhibition induced the functional recovery of the mitochondria as well as the metabolic reprogramming, which are two salient features that are altered in normal aging cells. Moreover, microarray analysis revealed that the up-regulated pathway upon ROCK inhibition is enriched for chromatin remodeling genes, which may play an important role in the alleviation of senescence-associated cell cycle arrest. Indeed, ROCK inhibition induced cellular proliferation, concomitant with the amelioration of senescent phenotype. Furthermore, the restorative effect by ROCK inhibition was observed in vivo as evidenced by the facilitated cutaneous wound healing. Taken together, our data indicate that ROCK inhibition might be utilized to ameliorate normal aging process and to treat age-related disease. [ABSTRACT FROM AUTHOR]

Pattern recognition receptors (PRRs) are part of the immune system. They can recognize pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs) and retinoic acid-inducible gene 1 (RIG-1)-like receptors (RLRs) are 2 types of PRR in the innate immune system. Double-stranded RNA (dsRNA) can exist as a PAMP, including dsRNA viruses. dsRNA is known as a ligand not only for TLR3 but also for RLRs, including melanoma differentiation-associated gene 5 and RIG-1. Collagen is the main structural protein in the extracellular space in the skin. Recently, it was reported that treatment of a synthetic dsRNA, poly(I:C), decreases procollagen expression in skin fibroblasts. However, signaling pathways involved in this process have not yet been fully elucidated. The present study further explored the underlying signaling pathways involved in the processes. It was demonstrated by western blotting that treatment of poly(I:C), but not another PAMP, Pam3CSK4, inhibited procollagen expression in cultured human skin fibroblasts. Treatment of poly(I:C) and Pam3CSK4 induced activation of the mitogen-activated protein kinases and the nuclear factor-κB pathways. However, only poly(I:C), but not Pam3CSK4, induced the activation of the interferon regulatory factor 3 (IRF3) pathway. By using specific inhibitors, it was demonstrated that inhibition of IRF3 pathway relieved poly(I:C)-induced procollagen reduction. In conclusion, IRF3 signaling pathway serves an important role in poly(I:C)-induced procollagen reduction in skin fibroblasts. This suggests that the IRF3 signaling pathway may be a key target for collagen regulation in the skin. [ABSTRACT FROM AUTHOR]

Exposure of the skin to ultraviolet ( UV) irradiation causes various consequences such as inflammation and photoageing. Galanin is an active neuropeptide expressed widely in the central nervous system and peripheral tissues including the skin. Galanin promotes or inhibits inflammation in a context-dependent manner, but its role in UV irradiation-induced responses in human skin was still unknown. UV irradiation induced a substantial expression of galanin in primary epidermal keratinocytes in vitro and in human epidermis in vivo. Galanin knock-down by si RNA transfection markedly inhibited UV irradiation-induced expression of matrix metalloproteinase ( MMP)-1, interleukin ( IL)-1β, IL-6 and cyclooxygenase ( COX)-2. Moreover, si RNA-mediated knock-down of GAL2, a principal galanin receptor in the skin, led to a considerable decrease in these mediators in keratinocytes. Collectively, our findings suggest that galanin is an important messenger between the neuroendocrine system and UV irradiation-damaged skin. [ABSTRACT FROM AUTHOR]

The multifaceted nature of senescent cell cycle arrest necessitates the targeting of multiple factors arresting or promoting the cell cycle. We report that co-inhibition of ATM and ROCK by KU-60019 and Y-27632, respectively, synergistically increases the proliferation of human diploid fibroblasts undergoing replicative senescence through activation of the transcription factors E2F1 and FOXM1. Time-course transcriptome analysis identified FOXM1 and E2F1 as crucial factors promoting proliferation. Co-inhibition of the kinases ATM and ROCK first promotes the G2/M transition via FOXM1 activation, leading to accumulation of cells undergoing the G1/S transition via E2F1 activation. The combination of both inhibitors increased this effect more significantly than either inhibitor alone, suggesting synergism. Our results demonstrate a FOXM1- and E2F1-mediated molecular pathway enhancing cell cycle progression in cells with proliferative potential under replicative senescence conditions, and treatment with the inhibitors can be tested for senomorphic effect in vivo. Inhibitors to ATM and ROCK kinases increases the proliferation via transcriptional changes in human diploid fibroblasts undergoing replicative senescence in a synergistic manner [ABSTRACT FROM AUTHOR]

• Ultraviolet (UV) irradiation is the main contributing factor for skin aging. • UV treatment decreases the expression of HDACs and SIRTs in dermal fibroblasts. • HDAC4 may regulate MMP-1 and type I procollagen expression through the activation of JNK pathways. 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). 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Background Ultraviolet (UV) radiation plays important roles in various skin diseases including premature aging and cancer. UV has been shown to regulate the expressions of many genes including matrix metalloproteinases (MMPs). Gasdermin C (GSDMC) belongs to Gasdermin family and is known to be expressed in the epithelial cells of many tissues including the skin. However, the functions of GSDMC remain poorly understood. Objective We aimed to investigate the role of GSDMC in UV-induced MMP-1, MMP-3, and MMP-9 expressions in human skin keratinocytes. Methods Primary human skin keratinocytes and an immortalized human skin keratinocyte cell line (HaCaT cells) were irradiated with UV. Knockdown and overexpression of GSDMC were performed to study the effect of GSDMC. The mRNA and protein levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Results We found that GSDMC expression is increased by UV irradiation in human skin keratinocytes. Further studies showed that GSDMC expression is increased at relatively late time points after UV irradiation and that this GSDMC induction plays important roles in the expressions of MMP-1, but not of MMP-3 and MMP-9, and the activations of ERK and JNK induced by UV. In addition, we found that overexpression of GSDMC increases the MMP-1 expression and the activities of ERK and JNK and that GSDMC-induced MMP-1 expression is suppressed by inhibition of ERK or JNK activities. Conclusions Our results suggest that GSDMC is increased by UV radiation and contributes to UV-induced MMP-1 expression through the activation of ERK and JNK pathways. [ABSTRACT FROM AUTHOR]

Background Transient receptor potential type 1 (TRPV1) can be activated by ultraviolet (UV) irradiation, and mediates UV-induced matrix metalloproteinase (MMP)-1 and proinflammatory cytokines in keratinocytes. Various chemicals and compounds targeting TRPV1 activation have been developed, but are not in clinical use mostly due to their safety issues. Objective We aimed to develop a novel TRPV1-targeting peptide to inhibit UV-induced responses in human skin. Methods We designed and generated a novel TRPV1 inhibitory peptide (TIP) which mimics the specific site in TRPV1 (aa 701-709: Gln-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr, QRAITILDT), Thr 705 , and tested its efficacy of blocking UV-induced responses in HaCaT, mouse, and human skin. Results TIP effectively inhibited capsaicin-induced calcium influx and TRPV1 activation. Treatment of HaCaT with TIP prevented UV-induced increases of MMP-1 and pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-α. In mouse skin in vivo , TIP inhibited UV-induced skin thickening and prevented UV-induced expression of MMP-13 and MMP-9. Moreover, TIP attenuated UV-induced erythema and the expression of MMP-1, MMP-2, IL-6, and IL-8 in human skin in vivo . Conclusion The novel synthetic peptide targeting TRPV1 can ameliorate UV-induced skin responses in vitro and in vivo , providing a promising therapeutic approach against UV-induced inflammation and photoaging. [ABSTRACT FROM AUTHOR]

Vasoactive intestinal peptide (VIP), one of the major skin neuropeptides, has been suggested to have active roles in the pathogenesis of inflammatory skin disorders such as atopic dermatitis and psoriasis, which can commonly cause post-inflammatory hyperpigmentation. However, the effect of VIP on melanogenesis remains unknown. In this study, we showed that the melanin contents, tyrosinase activity, and gene expression of tyrosinase and microphthalmia-associated transcription factor (MITF) were significantly increased by treatment with VIP in B16F10 mouse melanoma cells and the stimulatory melanogenic effect was further examined in human epidermal melanocytes (HEMns). In addition, phosphorylated levels of CRE-binding protein (CREB) and protein kinase A (PKA) were markedly increased after VIP treatment, but not p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), or Akt, indicating the possible PKA-CREB signaling pathway involved in VIP-induced melanogenesis. This result was further verified by the fact that VIP induced increased melanin synthesis, and protein levels of phosphorylated CREB, MITF, tyrosinase were significantly attenuated by H89 (a specific PKA inhibitor). These data suggest that VIP-induced upregulation of tyrosinase through the CREB-MITF signaling pathway plays an important role in finding new treatment strategy for skin inflammatory diseases related pigmentation disorders. [ABSTRACT FROM AUTHOR]

Ultraviolet ( UV) irradiation on skin triggers photoageing-related phenotypes such as formation of wrinkles. UV ray upregulates matrix metalloproteinase-1 ( MMP-1), which in turn degrades extracellular matrix proteins, mostly collagens. Serum amyloid A1 ( SAA1) is an acute-phase protein of which plasma concentration increases in response to inflammation. Although the expression of SAA1 in the skin was reported, its function in the skin is yet to be studied. In this research, we found that the expression of SAA1 was increased in acute UV-irradiated buttock skin and photoaged forearm skin in vivo. UV irradiation also increased SAA1 in normal human epidermal keratinocytes ( NHEK), and treatment of recombinant human SAA1 (rh SAA1) induced MMP-1 in normal human dermal fibroblasts ( NHDF) but not in NHEK. Next, we demonstrated that NHDF treated with UV-irradiated keratinocyte-conditioned media showed the increased MMP-1 expression; however, this increase of MMP-1 in NHDF was inhibited by knockdown of SAA1 in NHEK. In addition, knockdown of Toll-like receptor 4 ( TLR4) inhibited rh SAA1-induced MMP-1 expression in NHDF. Taken together, our data showed that UV-induced SAA1 production in NHEK, and this secreted SAA1 induced MMP-1 expression in NHDF in a paracrine manner through TLR4 signalling pathway. Therefore, our results suggest that SAA1 can be a potential mediator for UV-induced MMP-1 expression in human skin. [ABSTRACT FROM AUTHOR]

Background Ultraviolet (UV) irradiation can result in premature skin aging (photoaging) which is characterized by decreased expression of collagen and increased expression of matrix metalloproteinases (MMPs). Double-stranded RNAs (dsRNAs) can be generated at various conditions including virally infected cells or UV-damaged skin cells. Recent studies have shown that a synthetic dsRNA, polyinosinic-polycytidylic acid (poly(I:C)), can reduce procollagen expression in human skin fibroblasts. However, little is known about the effect of poly(I:C) on the expression of MMPs in skin fibroblasts and its underlying mechanisms. Objective We examined the effect of poly(I:C) on MMP-1, -2, and -3 expressions in human skin fibroblasts. Then, we further explored the underlying signaling pathways involved in the processes. Methods Human skin fibroblasts were treated with poly(I:C) for the indicated times in the presence or the absence of various chemical inhibitors or small interfering RNAs (siRNAs) at the indicated concentrations. Protein and mRNA levels of various target molecules were examined by Western blotting and quantitative real-time PCR, respectively. Results Poly(I:C) induced MMP-1, -2, and -3 expressions, which were dependent on TLR3. Poly(I:C) also induced activations of the mitogen-activated protein kinases (MAPKs), the nuclear factor-kappaB (NF-κB) and the interferon regulatory factor 3 (IRF3) pathways. By using specific inhibitors, we found that poly(I:C)-induced expressions of MMP-1, -2, and -3 were differentially regulated by these signaling pathways. In particular, we found that the inhibition of IRF3 signaling pathways attenuated poly(I:C)-induced expressions of all the three MMPs. Conclusion Our data show that the expressions of MMP-1, -2, and -3 are induced by poly(I:C) through various signaling pathways in human skin fibroblasts and suggest that TLR3 and/or IRF3 may be good targets for regulating the expressions of MMP-1, -2, and -3 induced by dsRNAs. [ABSTRACT FROM AUTHOR]

[Display omitted] Photoaging mainly occurs due to ultraviolet (UV) radiation, and is accompanied by increased secretion of matrix metalloproteinases (MMPs) and degradation of collagen. UV radiation induces cell senescence in the skin; however, the role of senescent cells in photoaging remains unclear. Therefore, to elucidate the role of senescent cells in photoaging, we evaluated the effect of senolytics in a photoaging mouse model and investigated the underlying mechanism of their antiaging effect. Both UV-induced senescent human dermal fibroblasts and a photoaging mouse model, ABT-263 and ABT-737, demonstrated senolytic effects on senescent fibroblasts. Moreover, we found that several senescence-associated secretory phenotype factors, such as IL-6, CCL5, CCL7, CXCL12, and SCF, induced MMP-1 expression in dermal fibroblasts, which decreased after treatment with ABT-263 and ABT-737 in vivo and in vitro. Both senolytic drugs attenuated the induction of MMPs and decreased collagen density in the photoaging mouse model. Our data suggest that senolytic agents reduce UV-induced photoaging, making strategies for targeting senescent dermal fibroblasts promising options for the treatment of photoaging. • Secretory phenotypes from UV-induced senescent fibroblasts induced MMP-1 expression. • Treatment with senolytic drugs attenuated collagen degradation in photoaged mice. • Elimination of senescent cells in photoaged skin exhibited an antiaging effect. [ABSTRACT FROM AUTHOR]

Background Biglycan (BGN) is a proteoglycan composed of a 42-kDa core protein and two glycosaminoglycan (GAG) chains, and known to be involved in structural, space-filling functions and many physiological regulations in the skin. Objective To investigate ultraviolet (UV) irradiation-induced changes of BGN protein and its GAG chain synthesis in cultured human dermal fibroblasts. Methods UV irradiation-induced or xylosyltransferase (XYLT) 1 siRNA-mediated smaller-sized protein bands detected by Western blot using BGN antibodies were identified as monoglycosylated forms of BGN, using BGN siRNA-mediated knockdown and chondroitinase ABC (ChABC). Differential activity of XYLT1 and 2 on BGN core protein was investigated by size shift of S42A- and S47A-BGN mutants to core protein size caused by XYLT1 siRNA transfection or UV irradiation. Results After UV irradiation, intact form of BGN protein (I-BGN) and core protein form were reduced in cultured fibroblasts, but other smaller-sized bands were observed to be increased. These smaller-sized ones were reduced by transfection of BGN siRNA, and shifted to the core protein size by treatment with ChABC, suggesting that they are defectively-glycosylated forms of BGN (D-BGN) protein. UV irradiation also decreased mRNA expression levels of XYLT1 and 2, which are responsible for initiation of GAG chain synthesis. UV-mediated reduction of XYLT1 expression was much stronger than that of XYLT2. Furthermore, siRNA-mediated down-regulation of XYLT1 resulted in the increase of D-BGN and the decrease of I-BGN, while down-regulation of XYLT2 resulted in no change of D-BGN and I-BGN, suggesting that the XYLT1 may react with both GAG-attaching serine sites of BGN; however, XYLT2 may prefer to react one of them. Another dermatan sulfate (DS) proteoglycan, decorin, showed no or a little change of its molecular weight by UV irradiation or XYLT1 siRNA transfection, suggesting that DS synthesis may not be a critical factor in formation of D-BGN. Co-transfection with XYLT1, 2 siRNAs and wild-type or mutant forms of BGN overexpression vectors revealed that S42A-BGN showed size reduction to core protein size by XYLT1 downregulation, but S47A-BGN did not, suggesting that XYLT2 can react only with S42 on BGN core protein. With UV irradiation, both S42A-BGN and S47A-BGN showed size reduction, which is probably because UV-caused downregulation of both XYLTs and overexpression condition resulted in incomplete glycosylation and secretion. Conclusions UV irradiation-induced increase of BGN monoglycosylated forms in cultured human dermal fibroblasts is resulted from dominance of XYLT2 activity, which acts only at S42 on BGN core protein, caused by UV-mediated stronger reduction of XYLT1. [ABSTRACT FROM AUTHOR]

Abstract: Background: Thrombospondin-1 (TSP-1) is a matricellular glycoprotein and recognized as an inhibitor of angiogenesis and an activator of transforming growth factor-β (TGF-β). Although TSP-1 expression has been shown to be regulated by various stimuli including UV in some types of cell, more work need to be done to understand the regulation of TSP-1 expression and its functional significances in many other types of cell. Objective: In this study, we investigated the effect of UV on TSP-1 expression in human skin dermis and dermal fibroblasts and the role of TSP-1 on the type I procollagen expression after UV exposure. Methods: Human buttock skin and human dermal fibroblasts were irradiated with UV. The mRNA and the protein levels of TSP-1 or type I procollagen were measured by real-time polymerase chain reaction and Western blotting, respectively. Results: We found that UV irradiation increased TSP-1 expression at the mRNA and protein levels in human skin dermis and dermal fibroblasts. UV-induced TSP-1 expression was greatly suppressed by inhibition of the PI3K, Akt, or mTOR pathways. The inhibition of TSP-1 activity by a blocking peptide or suppression of TSP-1 expression by specific TSP-1 small interfering RNA augmented the UV-induced decrease of type I procollagen expression. Conclusion: Our results suggest that UV-induced TSP-1 plays an important role on alleviating and/or recovering the type I procollagen expression downregulated by UV in human dermal fibroblasts. [Copyright &y& Elsevier]

Abstract: Background: Although fatty acids are known to be important in various skin functions, their roles on photoaging in human skin are poorly understood. Objective: We investigated the alteration of lipid metabolism in the epidermis by photoaging and acute UV irradiation in human skin. Methods: UV irradiated young volunteers (21–33 years, n =6) and elderly volunteers (70–75 years, n =7) skin samples were obtained by punch biopsy. Then the epidermis was separated from dermis and lipid metabolism was investigated. Results: We observed that the amounts of free fatty acids (FFA) and triglycerides (TG) in the epidermis of photoaged or acutely UV irradiated human skin were significantly decreased. The expressions of genes related to lipid synthesis, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), sterol regulatory element binding proteins (SREBPs), and peroxisome proliferator-activated receptors (PPARγ) were also markedly decreased. To elucidate the significance of these changes of epidermal lipids in human skin, we investigated the effects of TG or various inhibitors for the enzymes involved in TG synthesis on the expression of matrix metalloproteinase-1 (MMP-1) in cultured human epidermal keratinocytes. We demonstrated that triolein (TG) reduced basal and UV-induced MMP-1 mRNA expression. In addition, each inhibitor for various lipid synthesis enzymes, such as TOFA (ACC inhibitor), cerulenin (FAS inhibitor) and trans-10, cis-12-CLA (SCD inhibitor), increased the MMP-1 expression significantly in a dose-dependent manner. We also demonstrated that triolein could inhibit cerulenin-induced MMP-1 expression. Furthermore, topical application of triolein (10%) significantly prevented UV-induced MMP-13, COX-2, and IL-1β expression in hairless mice. Conclusion: Our results suggest that TG and FFA may play important roles in photoaging of human skin. [Copyright &y& Elsevier]