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1.
Br J Dermatol ; 178(3): 749-760, 2018 03.
Article in English | MEDLINE | ID: mdl-28815554

ABSTRACT

BACKGROUND: Striae gravidarum (SG), or stretch marks of pregnancy, begin as erythematous streaks and mature into hypopigmented atrophic bands. OBJECTIVES: In order to investigate molecular alterations that may promote atrophy of SG, we investigated dermal type I collagen fibrils, which provide human skin with support. METHODS: We obtained skin samples of recently developed, erythematous abdominal SG from pregnant women. To examine the organization of collagen fibrils, second-harmonic generation imaging was performed using multiphoton microscopy. Immunostaining was used to determine protein expression and localization of type I procollagen, the precursor of type I collagen fibrils. Real-time polymerase chain reaction was used to determine gene expression levels. RESULTS: In control (hip) and stretched normal-appearing perilesional abdominal skin, dermal collagen fibrils were organized as tightly packed, interwoven bundles. In SG, collagen bundles appeared markedly separated, especially in the mid-to-deep dermis. In the spaces separating these bundles, loosely packed wavy collagen fibrils lacking organization as bundles were present. These disorganized fibrils persisted into the postpartum period and failed to form densely packed bundles. Numerous large fibroblasts displaying type I procollagen expression were in close proximity to the disorganized fibrils, suggesting that the fibrils are newly synthesized. Supporting this possibility, immunostaining and gene expression of type I procollagen were increased throughout the dermis of SG. CONCLUSIONS: Early SG display marked separation of collagen bundles and emergence of disorganized collagen fibrils that fail to form bundles. These alterations may reflect ineffective repair of collagen bundles disrupted by intense skin stretching. Persistent disruption of the collagenous extracellular matrix likely promotes formation and atrophy of SG.


Subject(s)
Collagen Diseases/pathology , Pregnancy Complications/pathology , Striae Distensae/pathology , Case-Control Studies , Collagen Diseases/metabolism , Collagen Type I/metabolism , Female , Fibrillar Collagens/physiology , Fibroblasts/metabolism , Humans , Pregnancy , Pregnancy Complications/metabolism , Procollagen/biosynthesis , Skin/blood supply , Striae Distensae/metabolism , Young Adult
2.
Int J Cosmet Sci ; 39(1): 56-65, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27261203

ABSTRACT

OBJECTIVE: Retinoic acid has been shown to improve the aged-appearing skin. However, less is known about the anti-ageing effects of retinol (ROL, vitamin A), a precursor of retinoic acid, in aged human skin in vivo. This study aimed to investigate the molecular basis of ROL anti-ageing properties in naturally aged human skin in vivo. METHODS: Sun-protected buttock skin (76 ± 6 years old, n = 12) was topically treated with 0.4% ROL and its vehicle for 7 days. The effects of topical ROL on skin epidermis and dermis were evaluated by immunohistochemistry, in situ hybridization, Northern analysis, real-time RT-PCR and Western analysis. Collagen fibrils nanoscale structure and surface topology were analysed by atomic force microscopy. RESULTS: Topical ROL shows remarkable anti-ageing effects through three major types of skin cells: epidermal keratinocytes, dermal endothelial cells and fibroblasts. Topical ROL significantly increased epidermal thickness by stimulating keratinocytes proliferation and upregulation of c-Jun transcription factor. In addition to epidermal changes, topical ROL significantly improved dermal extracellular matrix (ECM) microenvironment; increasing dermal vascularity by stimulating endothelial cells proliferation and ECM production (type I collagen, fibronectin and elastin) by activating dermal fibroblasts. Topical ROL also stimulates TGF-ß/CTGF pathway, the major regulator of ECM homeostasis, and thus enriched the deposition of ECM in aged human skin in vivo. 0.4% topical ROL achieved similar results as seen with topical retinoic acid, the biologically active form of ROL, without causing noticeable signs of retinoid side effects. CONCLUSION: 0.4% topical ROL shows remarkable anti-ageing effects through improvement of the homeostasis of epidermis and dermis by stimulating the proliferation of keratinocytes and endothelial cells, and activating dermal fibroblasts. These data provide evidence that 0.4% topical ROL is a promising and safe treatment to improve the naturally aged human skin.


Subject(s)
Aging/drug effects , Vitamin A/pharmacology , Collagen/metabolism , Connective Tissue Growth Factor/metabolism , Humans , Microscopy, Atomic Force , Skin/blood supply , Skin/cytology , Skin/metabolism , Transforming Growth Factor beta/metabolism
3.
Br J Dermatol ; 173(6): 1420-30, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26179468

ABSTRACT

BACKGROUND: Striae gravidarum (SG), or 'stretch marks' of pregnancy, begin as erythematous streaks, and mature over months to years to become permanent scar-like bands that may be hypopigmented, atrophic and lax. OBJECTIVES: To investigate early molecular alterations that may promote laxity of mature SG, we investigated the dermal elastic fibre network, which provides human skin with elastic properties. METHODS: We obtained skin samples of newly developed, erythematous abdominal SG in healthy pregnant women. The elastic fibre network was examined by Verhoeff elastic staining and immunofluorescence staining of skin sections. Gene expression was measured by real-time polymerase chain reaction. RESULTS: The normal elastic fibre network appeared markedly disrupted in SG, compared with perilesional abdominal skin or control (normal-appearing hip skin). This disruption was accompanied by the emergence of short, disorganized, thin, thread-like 'fibrils', which were observed prominently in the mid-to-deep dermis. These fibrils were rich in tropoelastin (the main component of normal elastic fibres), and persisted into the postpartum period without forming normal-appearing elastic fibres. The emergence of these fibrils was accompanied by increased gene expression of tropoelastin and fibrillin-1, but not other elastic fibre components, including fibrillin-2 and fibulin-1, -2 or -5. CONCLUSIONS: In early SG, the elastic fibre network appears markedly disrupted, and newly synthesized tropoelastin-rich fibrils emerge, likely as a result of uncoordinated synthesis of elastic fibre components. Because they are thin and disorganized, tropoelastin-rich fibrils likely do not function as normal elastic fibres do. These observations provide the foundations for elucidating pathogenic mechanisms by which laxity may develop in SG.


Subject(s)
Elastic Tissue/pathology , Striae Distensae/pathology , Collagen Diseases/pathology , Elastic Tissue/metabolism , Female , Humans , Pregnancy , Puerperal Disorders/metabolism , Puerperal Disorders/pathology , Striae Distensae/metabolism , Tropoelastin/metabolism , Young Adult
5.
Br J Dermatol ; 169(2): 406-11, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23495851

ABSTRACT

BACKGROUND: Genetic predisposition to psoriasis, an inflammatory skin disease affecting 0·2-4% of the world population, is well established. Thus far, 41 psoriasis susceptibility loci reach genome-wide significance (P ≤ 5 × 10(-8) ). Identification of genetic susceptibility loci in diverse populations will help understand the underlying biology of psoriasis susceptibility. OBJECTIVES: The primary objective of this study was to examine psoriasis susceptibility associations previously reported in Chinese and caucasian populations in a Pakistani cohort. METHODS: Blood samples and phenotype data were collected from psoriasis cases and controls in Islamabad, Pakistan. DNA was isolated and genotypes of selected susceptibility markers were determined. The data were analysed using χ(2) tests or logistic regression for psoriasis association. RESULTS: HLA-Cw6 showed the strongest association [odds ratio (OR) 2·43, P = 2·3 × 10(-12) ]. HLA-Cw1 showed marginally significant association (OR 1·66, P = 0·049), suggesting that the HLA-Cw1-B46 risk haplotype may be present in the Pakistani population. Three other loci (IL4/IL13, NOS2, TRAF3IP2) showed nominally significant association (P < 0·05). CONCLUSIONS: HLA-Cw6 is strongly associated with psoriasis susceptibility in the Pakistani population, as has been found in every other population studied. In addition, HLA-Cw1 showed marginal association, reflecting the relative geographical proximity and thus likely genetic relatedness to other populations in which the HLA-Cw1-B46 haplotype is known to be associated. A larger cohort and a denser marker set will be required for further analysis of psoriasis associations in the South Asian population.


Subject(s)
Genetic Loci/genetics , Psoriasis/genetics , Adaptor Proteins, Signal Transducing , Adult , Age of Onset , Female , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Genotype , HLA-C Antigens/genetics , Haplotypes , Humans , Interleukin-13/genetics , Male , Nitric Oxide Synthase Type II/genetics , Pakistan/ethnology , Polymorphism, Single Nucleotide , Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/genetics
6.
Br J Dermatol ; 167(1): 92-102, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22458549

ABSTRACT

BACKGROUND: Psoriasis is a Th17/Th1-mediated skin disease that often responds to antitumour necrosis factor (TNF)-α therapies, such as etanercept. OBJECTIVES: To better define mechanisms by which etanercept improves psoriasis and to gain insight into disease pathogenesis. METHODS: We investigated the early biochemical and cellular effects of etanercept on skin lesions in responder patients prior to substantial clinical improvement (≤ 4 weeks). RESULTS: By 1 week, etanercept acutely suppressed gene expression of the interleukin (IL)-20 subfamily of cytokines (IL-19, IL-20, IL-24), which were found to be predominantly epidermis-derived and which are implicated in stimulating epidermal hyperplasia. Additionally, by 1 week of therapy, suppression of other keratinocyte-derived products (chemokines, antimicrobial proteins) occurred, while suppression of epidermal regenerative hyperplasia occurred within 1-3 weeks. Th17 elements (IL-23p19, IL-12p40, IL-17A, IL-22) were suppressed by 3-4 weeks. In vitro, TNF-α and IL-17A coordinately stimulated the expression of the IL-20 subfamily in normal keratinocytes. CONCLUSIONS: Based on the rapid suppression of regenerative hyperplasia, chemokines and other keratinocyte-derived products, including the IL-20 subfamily, we propose that epidermal activation is a very early target of etanercept. As many of these keratinocyte markers are stimulated by TNF-α, their rapid downregulation is likely to reflect etanercept's antagonism of TNF-α. Additionally, decreased epidermal hyperplasia might result specifically from acute suppression of the IL-20 subfamily, which is also a likely consequence of etanercept's antagonism of TNF-α. Thus, the IL-20 subfamily has potential importance in the pathogenesis of psoriasis and therapeutic response to etanercept.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Epidermis/pathology , Immunoglobulin G/therapeutic use , Interleukins/metabolism , Psoriasis/drug therapy , Receptors, Tumor Necrosis Factor/therapeutic use , Adolescent , Adult , Aged , Dendritic Cells/physiology , Down-Regulation , Epidermis/metabolism , Epidermis/physiology , Etanercept , Humans , Hyperplasia/metabolism , Keratinocytes/physiology , Lymphocyte Activation/physiology , Middle Aged , Regeneration/physiology , T-Lymphocytes/physiology , Treatment Outcome , Tumor Necrosis Factor-alpha/physiology , Young Adult
7.
Clin Pharmacol Ther ; 89(1): 34-43, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21107316

ABSTRACT

The quest for youth and beauty is an ongoing one. No organ conveys youth and beauty to the extent that skin does. Advances in research over the past several decades have yielded a tremendous amount of information on the molecular pathways involved in both intrinsic aging (natural) and extrinsic aging (photoaging). In this article, we aim to describe the molecular pathways that lead to an aged appearance and to describe the latest and most commonly employed drugs and procedures to reverse skin aging and stimulate the production of new collagen. With enhanced understanding of these molecular pathways, drugs and devices used to treat aging skin can be more precisely tuned.


Subject(s)
Skin Aging/drug effects , Skin Aging/pathology , Skin Physiological Phenomena/drug effects , Skin/drug effects , Skin/physiopathology , Aged , Aged, 80 and over , Animals , Beauty , Collagen/metabolism , Cosmetic Techniques , Dermatologic Surgical Procedures , Humans , Skin/metabolism
8.
Br J Dermatol ; 163(4): 757-68, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20854401

ABSTRACT

BACKGROUND: Nonablative fractionated laser resurfacing improves the texture of treated skin, but little is known about the molecular mechanisms that underlie clinical improvements. OBJECTIVES: We sought to examine and quantify the time course and magnitude of dermal matrix changes that occur in response to nonablative fractionated laser resurfacing, with the dual goals of better understanding the molecular mechanisms that underlie clinical improvements and of gaining knowledge that will enable evidence-based treatment parameter optimization. METHODS: Twenty patients (mean age 58 years) with photodamaged skin were focally treated on dorsal forearms with a nonablative fractionated laser. Serial skin samples were obtained at baseline and at various times after treatment. Biopsies were examined with real-time polymerase chain reaction technology and immunohistochemical techniques. RESULTS: Laser treatment resulted in an initial inflammatory response as indicated by statistically significant induction of proinflammatory cytokines (interleukin-1ß and tumour necrosis factor-α). This was followed by substantial increases in levels of several matrix metalloproteinases and later by significant induction of type I collagen. Dermal remodelling was noted with both low and high microbeam energy treatment parameters. CONCLUSIONS: Nonablative fractionated laser resurfacing induces a well-organized wound-healing response that leads to substantial dermal remodelling and collagen induction. Surprisingly, only minimal differences were observed between lower and higher microbeam energy settings. These data suggest that lower microbeam energy/higher microbeam density treatment parameters, which are generally better tolerated by patients, may yield dermal changes similar to those that result from higher microbeam energy/lower microbeam density treatment parameters.


Subject(s)
Dermatologic Surgical Procedures , Laser Therapy/methods , Wound Healing/physiology , Adult , Aged , Biopsy , Collagen Type I/biosynthesis , Collagen Type I/genetics , Collagen Type III/biosynthesis , Collagen Type III/genetics , Female , Gene Expression Regulation , Humans , Male , Matrix Metalloproteinases/metabolism , Middle Aged , Skin/metabolism , Skin/pathology , Skin Aging , Skin Physiological Phenomena , Young Adult
9.
Tissue Antigens ; 76(5): 387-97, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20604894

ABSTRACT

Earlier studies have shown that psoriasis in Japan and Thailand is associated with two different major histocompatibility complex (MHC) haplotypes - those bearing HLA-Cw6 and those bearing HLA-Cw1 and HLA-B46. In an independent case-control sample from Thailand, we confirmed the association of psoriasis with both haplotypes. No association was seen in Thai HLA-Cw1 haplotypes lacking HLA-B46, nor was HLA-Cw1 associated with psoriasis in a large Caucasian sample. To assess whether these risk haplotypes share a common origin, we sequenced genomic DNA from a Thai HLA-Cw1-B46 homozygote across the ∼300 kb MHC risk interval, and compared it with sequence of a HLA-Cw6-B57 risk haplotype. Three small regions of homology were found, but these regions share equivalent sequence similarity with one or more clearly non-risk haplotypes, and they contain no polymorphism alleles unique to all risk haplotypes. Differences in psoriasis phenotype were also observed, including lower risk of disease, greater nail involvement, and later age at onset in HLA-Cw1-B46 carriers compared with HLA-Cw6 carriers. These findings suggest locus heterogeneity at PSORS1 (psoriasis susceptibility 1), the major psoriasis susceptibility locus in the MHC, with HLA-Cw6 imparting risk in both Caucasians and Asians, and an allele other than HLA-Cw1 on the HLA-Cw1-B46 haplotype acting as an additional risk variant in East Asians.


Subject(s)
Genes, MHC Class I , Proteins/genetics , Psoriasis/genetics , Psoriasis/immunology , Asian People/genetics , Case-Control Studies , HLA-B Antigens/genetics , HLA-C Antigens/genetics , Haplotypes , Humans , Phenotype , Polymorphism, Single Nucleotide , Risk Factors , Thailand , White People/genetics
11.
Br J Cancer ; 98(10): 1646-52, 2008 May 20.
Article in English | MEDLINE | ID: mdl-18443597

ABSTRACT

Connective tissue damage and angiogenesis are both important features of tumour growth and invasion. Here, we show that endothelial cells maintained on a three-dimensional lattice of intact polymerised collagen formed a monolayer of cells with a cobblestone morphology. When the collagen was exposed to organ culture fluid from human basal cell tumours of the skin (containing a high level of active matrix metalloproteinase-1 (MMP-1)), degradation of the collagen matrix occurred. The major degradation products were the $3 over 4$- and $1 over 4$-sized fragments known to result from the action of MMP-1 on type I collagen. When endothelial cells were maintained on the partially degraded collagen, the cells organised into a network of vascular tubes. Pretreatment of the organ culture fluid with either tissue inhibitor of metalloproteinase-1 (TIMP-1) or neutralising antibody to MMP-1 prevented degradation of the collagen lattice and concomitantly inhibited endothelial cell organisation into the vascular network. Purified (activated) MMP-1 duplicated the effects of skin organ culture fluid, but other enzymes including MMP-9 (gelatinase B), elastase or trypsin failed to produce measurable fragments from intact collagen and also failed to promote vascular tube formation. Together, these studies suggest that damage to the collagenous matrix is itself an important inducer of new vessel formation.


Subject(s)
Blood Vessels/physiology , Collagen/metabolism , Connective Tissue/metabolism , Matrix Metalloproteinase 1/metabolism , Neovascularization, Physiologic , Electrophoresis, Polyacrylamide Gel , Humans , Matrix Metalloproteinase 9/metabolism , Microscopy, Electron, Scanning
12.
Br J Dermatol ; 157(2): 369-74, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17596167

ABSTRACT

BACKGROUND: Becocalcidiol is a vitamin D(3) analogue which has not caused hypercalcaemia or significant irritation in preclinical trials. OBJECTIVES: To evaluate the efficacy and safety of two dosing regimens of becocalcidiol ointment (low dose = 75 microg g(-1) once daily for 8 weeks; high dose = 75 microg g(-1) twice daily for 8 weeks) in the treatment of plaque-type psoriasis. METHODS: One hundred and eighty-five subjects with chronic plaque-type psoriasis affecting 2-10% of their body surface area took part in a multicentre, double-blind, parallel-group, vehicle-controlled, randomized controlled trial comparing topical application of placebo, becocalcidiol 75 microg g(-1) once daily (low dose) or becocalcidiol twice daily (high dose) for 8 weeks. Main outcomes included Physician's Static Global Assessment of Overall Lesion Severity (PGA) score; Psoriasis Symptom Severity (PSS) score; adverse events; and laboratory assessment. RESULTS: In the intent-to-treat population at week 8, high-dose becocalcidiol was statistically superior to vehicle [P = 0.002; 95% confidence interval (CI) 6.7-32.2], with 16 of 61 (26%) subjects achieving a PGA score of clear or almost clear. Greater improvement in PSS score was seen with high-dose becocalcidiol than with vehicle, but this result did not quite achieve statistical significance (P = 0.052; 95% CI -16.2 to 0.1). In all groups, therapy was safe and well tolerated, with fewer subjects experiencing irritation than is reported in studies using calcipotriol. CONCLUSIONS: Treatment with high-dose topical becocalcidiol for 8 weeks led to almost or complete clearing of moderate plaque-type psoriasis in over a quarter of patients. Therapy was safe and well tolerated.


Subject(s)
Dermatologic Agents/therapeutic use , Dihydroxycholecalciferols/therapeutic use , Psoriasis/drug therapy , Adult , Aged , Aged, 80 and over , Chronic Disease , Dermatologic Agents/administration & dosage , Dermatologic Agents/adverse effects , Dihydroxycholecalciferols/administration & dosage , Dihydroxycholecalciferols/adverse effects , Double-Blind Method , Drug Administration Routes , Female , Humans , Male , Middle Aged , Patient Compliance , Severity of Illness Index , Treatment Outcome
13.
J Med Genet ; 43(1): 12-7, 2006 Jan.
Article in English | MEDLINE | ID: mdl-15923274

ABSTRACT

BACKGROUND: A previous study identified two peaks of allelic association between psoriasis and single nucleotide polymorphisms (SNPs) mapping to distal chromosome 17q, including a disease associated SNP that leads to loss of a RUNX1 transcription factor binding site, and additional SNPs in the third intron of the RAPTOR gene. Another study found an association with SNPs in the RAPTOR gene, but not with the RUNX1 binding site polymorphism. METHODS: In an effort to confirm these observations, we genotyped 579 pedigrees containing 1285 affected individuals for three SNPs immediately flanking and including the RUNX1 binding site, and for three SNPs in the RAPTOR gene. RESULTS: Here we report further evidence for linkage to distal chromosome 17q, with a linkage peak mapping 1.7 cM distal to the RUNX1 binding site (logarithm of the odds 2.26 to 2.73, depending upon statistic used). However, we found no evidence for association to individual SNPs or haplotypes in either of the previously identified peaks of association. Power analysis demonstrated 80% power to detect significant association at genotype relative risks of 1.2 (additive and multiplicative models) to 1.5 (dominant and recessive models) for the RUNX1 binding site, and 1.3 to 1.4 for the RAPTOR locus under all models except dominant. CONCLUSIONS: Our data provide no support for the previously identified RUNX1 binding site or for the RAPTOR locus as genetic determinants of psoriasis, despite evidence for linkage of psoriasis to distal chromosome 17q.


Subject(s)
Binding Sites/genetics , Core Binding Factor Alpha 2 Subunit/genetics , Genetic Linkage , Genetic Predisposition to Disease , Polymorphism, Genetic , Proteins/genetics , Psoriasis/genetics , Adaptor Proteins, Signal Transducing , Chromosomes, Human, Pair 17/genetics , Haplotypes , Humans , Regulatory-Associated Protein of mTOR
14.
Arch Dermatol ; 137(11): 1447-54, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11708947

ABSTRACT

Accumulating evidence indicates that psoriasis is a multifactorial disorder caused by the concerted action of multiple disease genes in a single individual, triggered by environmental factors. Some of these genes control the severity of multiple diseases by regulating inflammation and immunity (severity genes), whereas others are unique to psoriasis. Various combinations of these genes can occur even within a single family, accounting in large measure for the many clinical manifestations of psoriasis. The disease-causing variants (alleles) of these genes probably arose early in the history of modern humans. As a result, psoriasis disease alleles are common in the general population, have a worldwide distribution, and often share the same ancestral chromosome with neutral alleles at adjacent loci. This phenomenon, called linkage disequilibrium, explains why psoriasis is strongly associated with HLA-Cw6 worldwide, although HLA-Cw6 is unlikely to be the disease allele. Many unaffected individuals carry 1 or more disease alleles, but lack other genetic and/or environmental factors necessary to produce disease. This explains why psoriasis develops in only about 10% of HLA-Cw6-positive individuals, and why genome-wide linkage scans for psoriasis and other multifactorial genetic disorders have not been uniformly successful. The Human Genome Project is rapidly generating a catalog of human DNA sequence variations. This resource has already allowed precise linkage disequilibrium mapping of the major histocompatibility complex psoriasis gene to just beyond HLA-C, toward HLA-A. This gene is likely to be identified soon. Further development and use of linkage disequilibrium resources will provide a powerful tool for the identification of the remaining psoriasis genes.


Subject(s)
Genetic Predisposition to Disease/genetics , Psoriasis/genetics , Genetic Heterogeneity , Genetic Markers , HLA-C Antigens/genetics , Humans , Linkage Disequilibrium
15.
Cutis ; 68(2): 135-42, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11534915

ABSTRACT

In extensive clinical studies and practical use since its US Food and Drug Administration approval in 1995, tretinoin emollient cream 0.05% has been shown to be safe and effective in the treatment of fine facial wrinkles, mottled hyperpigmentation, and skin roughness. To provide additional prescribing flexibility for various patient needs, a new lower concentration formulation, tretinoin cream 0.02% was chosen for further development. Two multicenter, randomized, double-blind, vehicle-controlled clinical., studies were conducted to evaluate the safety and efficacy of the lower concentration tretinoin formulation in the treatment of moderate-to-severe facial photodamage. Results indicate statistically significant improvement in fine wrinkling, coarse wrinkling, and yellowing with the use of tretinoin cream 0.02% at week-24 end point, compared with placebo. Therapy with tretinoin cream 0.02% was well tolerated overall and demonstrated a favorable safety profile. Both studies demonstrated that tretinoin cream 0.02% is safe and effective for the treatment of moderate-to-severe photodamaged facial skin.


Subject(s)
Facial Dermatoses/drug therapy , Skin Aging/drug effects , Tretinoin/administration & dosage , Administration, Topical , Adult , Aged , Dose-Response Relationship, Drug , Double-Blind Method , Emollients/administration & dosage , Esthetics , Female , Follow-Up Studies , Humans , Male , Middle Aged , Reference Values , Severity of Illness Index , Treatment Outcome
16.
Clin Geriatr Med ; 17(4): 643-59, v-vi, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11535421

ABSTRACT

Premature skin aging, or photoaging, results largely from repeated exposure to ultraviolet (UV) radiation from the sun. Photoaging is characterized clinically by wrinkles, mottled pigmentation, rough skin, and loss of skin tone; the major histologic alterations lie in dermal connective tissue. In recent years, a great deal of research has been done to explain the mechanism by which UV induces dermal damage. This research has enabled the identification of rational targets for photoaging prevention strategies. Moreover, studies that have elucidated photoaging pathophysiology have produced significant evidence that topical tretinoin (all-trans retinoic acid), the only agent approved so far for the treatment of photoaging, also works to prevent it. This article summarizes evidence mainly from studies of human volunteers that provide the basis for the current model of photoaging and the effects of tretinoin.


Subject(s)
Skin Aging/pathology , Skin Diseases/pathology , Collagen/biosynthesis , Humans , Keratolytic Agents/therapeutic use , Skin Aging/drug effects , Skin Aging/radiation effects , Skin Diseases/prevention & control , Tretinoin/therapeutic use , Ultraviolet Rays/adverse effects
17.
J Invest Dermatol ; 117(2): 219-26, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11511297

ABSTRACT

Humans express three distinct collagenases, MMP-1, MMP-8, and MMP-13, that initiate degradation of fibrillar type I collagen. We have previously reported that ultraviolet irradiation causes increased expression of MMP-1, but not MMP-13, in keratinocytes and fibroblasts in human skin in vivo. We report here that ultraviolet irradiation increases expression of MMP-8 in human skin in vivo. Western analysis revealed that levels of the full-length, 85 kDa proenzyme form of MMP-8 increased significantly within 8 h post ultraviolet irradiation (2 minimal erythema doses). Increased full-length MMP-8 protein was associated with infiltration into the skin of neutrophils, which are the major cell type that expresses MMP-8. Immunofluorescence revealed coexpression of MMP-8 and neutrophil elastase, a marker for neutrophils. Immunohistology demonstrated MMP-8 expression in neutrophils in the papillary dermis between 4 and 8 h post ultraviolet irradiation, and in the epidermis at 24 h post radiation. MMP-8 mRNA expression was not detected in nonirradiated or ultraviolet-irradiated human skin, indicating that increased MMP-8 following ultraviolet irradiation resulted from preexisting MMP-8 protein in infiltrating neutrophils. Pretreatment of skin with the glucocorticoid clobetasol, but not all-trans retinoic acid, significantly blocked ultraviolet-induced increases in MMP-8 protein levels, and neutrophil infiltration. In contrast, all-trans retinoic acid and clobetasol were equally effective in blocking ultraviolet induction of MMP-1 and degradation of collagen in human skin in vivo. Taken together, these data demonstrate that ultraviolet irradiation increases MMP-8 protein, which exists predominantly in a latent form within neutrophils, in human skin in vivo. Although ultraviolet irradiation induces both MMP-1 and MMP-8, ultraviolet-induced collagen degradation is initiated primarily by MMP-1, with little, if any, contribution by MMP-8.


Subject(s)
Matrix Metalloproteinase 8/metabolism , Skin Aging/physiology , Skin/enzymology , Skin/radiation effects , Ultraviolet Rays , Adult , Biopsy , Clobetasol/administration & dosage , Collagen/metabolism , Gene Expression/drug effects , Gene Expression/radiation effects , Glucocorticoids/administration & dosage , Humans , Keratolytic Agents/administration & dosage , Matrix Metalloproteinase 1/analysis , Matrix Metalloproteinase 1/genetics , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 8/analysis , Matrix Metalloproteinase 8/genetics , Neutrophils/enzymology , Neutrophils/radiation effects , RNA, Messenger/analysis , Skin/pathology , Skin Aging/drug effects , Skin Aging/pathology , Tretinoin/administration & dosage
19.
J Biol Chem ; 276(28): 26349-56, 2001 Jul 13.
Article in English | MEDLINE | ID: mdl-11320083

ABSTRACT

Transforming growth factor-beta (TGF-beta) is a multi-functional cytokine that regulates cell growth and differentiation. Cellular responses to TGF-beta are mediated through its cell surface receptor complex, which activates transcription factors Smad2 and Smad3. Here we report that UV irradiation of mink lung epithelial cells causes near complete inhibition of TGF-beta-induced Smad2/3-mediated gene expression. UV irradiation inhibited TGF-beta-induced phosphorylation of Smad2 and subsequent nuclear translocation and DNA binding of Smad2/3. Specific cell surface binding of TGF-beta was substantially reduced after UV irradiation. This loss of TGF-beta binding resulted from UV-induced down-regulation of TGF-beta type II receptor (T beta RII) mRNA and protein. UV irradiation significantly inhibited T beta RII promoter reporter constructs, indicating that UV reduction of T beta RII expression involved transcriptional repression. In contrast to its effects on T beta RII, UV irradiation rapidly induced Smad7 mRNA and protein. Smad7 is known to antagonize activation of Smad2/3 and thereby block TGF-beta-dependent gene expression. UV irradiation stimulated Smad7 promoter reporter constructs, indicating that increased Smad7 expression resulted, at least in part, from increased transcription. Overexpression of Smad7 protein to the level induced by UV irradiation inhibited TGF-beta-induced gene expression 30%. Maintaining T beta RII levels by overexpression of T beta RII prevented UV inhibition of TGF-beta responsiveness. Taken together, these data indicate that UV irradiation blocks cellular responsiveness to TGF-beta through two mechanisms that impair TGF-beta receptor function. The primary mechanism is down-regulation of T beta RII, and the secondary mechanism is induction of Smad7.


Subject(s)
DNA-Binding Proteins/physiology , Epithelial Cells/physiology , Epithelial Cells/radiation effects , Receptors, Transforming Growth Factor beta/physiology , Trans-Activators/physiology , Transforming Growth Factor beta/pharmacology , Animals , Cell Line , Down-Regulation , Protein Serine-Threonine Kinases , Receptor, Transforming Growth Factor-beta Type II , Signal Transduction , Smad7 Protein , Transforming Growth Factor beta/physiology , Ultraviolet Rays
20.
Clin Exp Dermatol ; 26(1): 79-83, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11260185

ABSTRACT

Psoriasis is a chronic inflammatory skin disease with a strong genetic component. Linkage studies have identified several susceptibility loci for psoriasis including a region on chromosome 1q21 termed the 'epidermal differentiation complex'. At least 20 genes involved in epidermal differentiation and proliferation have been mapped to this region including S100A2, a gene known to be over-expressed in psoriasis lesions. In the course of cloning and sequencing several S100A2 cDNAs, we identified an A/G (Asn62Ser) polymorphism at nucleotide 185 of the S100A2 coding region. To determine whether this polymorphism is associated with psoriasis, we tested DNA from 38 unrelated normal and 40 unrelated psoriatic individuals. The 185G allele was present in 148 of the 156 chromosomes analysed, giving an allele frequency of 94.9%. All of the remaining chromosomes carried 185A. There was no significant difference in the allele distribution between normal and psoriatic individuals (normals 72G, 4A; psoriatics 76G, 4A; P = 1.00 by Fisher's exact test). Our data explain conflicting results in the literature regarding the sequence of S100A2 but provide no support for a direct causal role for S100A2 in psoriasis.


Subject(s)
Chemotactic Factors/genetics , Psoriasis/genetics , S100 Proteins/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Child , Female , Genetic Markers , Humans , Male , Middle Aged , Polymerase Chain Reaction , Polymorphism, Genetic , Sequence Analysis, DNA
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