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Biomedical subjects

John J Voorhees

Publications and source records attributed to John J Voorhees.

At least 19 recordsLinked to original sources
PubMed2006

Oxidative inhibition of receptor-type protein-tyrosine phosphatase kappa by ultraviolet irradiation activates epidermal growth factor receptor in human keratinocytes.

Ultraviolet (UV) irradiation rapidly increases tyrosine phosphorylation (i.e. activates) of epidermal growth factor receptors (EGFR) in human skin. EGFR-dependent signaling pathways drive increased expression of matrix metalloproteinases, whose actions fragment collagen and elastin fibers, the primary structural protein components in skin connective tissue. Connective tissue fragmentation, which results from chronic exposure to solar UV irradiation, is a major determinant of premature skin aging (photoaging). UV irradiation generates reactive oxygen species, which readily react with conserved cysteine residues in the active site of protein-tyrosine phosphatases (PTP). We report here that EGFR activation by UV irradiation results from oxidative inhibition of receptor type PTP-kappa (RPTP-kappa). RPTP-kappa directly counters intrinsic EGFR tyrosine kinase activity, thereby maintaining EGFR in an inactive state. Reversible, oxidative inactivation of RPTP-kappa activity by UV irradiation shifts the kinase-phosphatase balance in favor of EGFR activation. These data delineate a novel mechanism of EGFR regulation and identify RPTP-kappa as a key molecular target for antioxidant protection against skin aging.

Animals↗
PubMed2006

The effects of laser-mediated hair removal on immunohistochemical staining properties of hair follicles.

BACKGROUND: The mechanisms involved in laser-mediated hair removal remain unclear. One means of reducing hair growth is alteration of follicular stem cells. OBJECTIVE: We sought to examine the effects of laser hair removal on the immunohistochemical staining properties of human hair follicles, including the putative stem cells of the bulge region. METHODS: Treatment of unwanted axillary hair was performed on one side using an 800 nm-wavelength diode laser and on the other side using a 1064 nm-wavelength neodymium:yttrium-aluminum-garnet laser. Serial skin samples were obtained at baseline and various times after treatment and stained using immunohistochemical techniques. RESULTS: Hair shafts were thermally altered, but the immunostaining properties of much of the follicle, including the bulge region, remained generally unchanged. LIMITATIONS: This study only addressed the acute immunohistochemical changes found after a single treatment using specific laser parameters. CONCLUSIONS: Laser-mediated hair removal does not appear to work by frank destruction of follicular stem cells. Other mechanisms including functional alteration of these cells may underlie the clinical efficacy of the procedure.

Adult↗
PubMed2006

Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.

Previous studies have narrowed the interval containing PSORS1, the psoriasis-susceptibility locus in the major histocompatibility complex (MHC), to an approximately 300-kb region containing HLA-C and at least 10 other genes. In an effort to identify the PSORS1 gene, we cloned and completely sequenced this region from both chromosomes of five individuals. Two of the sequenced haplotypes were associated with psoriasis (risk), and the other eight were clearly unassociated (nonrisk). Comparison of sequence of the two risk haplotypes identified a 298-kb region of homology, extending from just telomeric of HLA-B to the HCG22 gene, which was flanked by clearly nonhomologous regions. Similar haplotypes cloned from unrelated individuals had nearly identical sequence. Combinatorial analysis of exonic variations in the known genes of the candidate interval revealed that HCG27, PSORS1C3, OTF3, TCF19, HCR, STG, and HCG22 bore no alleles unique to risk haplotypes among the 10 sequenced haplotypes. SPR1 and SEEK1 both had messenger RNA alleles specific to risk haplotypes, but only HLA-C and CDSN yielded protein alleles unique to risk. The risk alleles of HLA-C and CDSN (HLA-Cw6 and CDSN*TTC) were genotyped in 678 families with early-onset psoriasis; 620 of these families were also typed for 34 microsatellite markers spanning the PSORS1 interval. Recombinant haplotypes retaining HLA-Cw6 but lacking CDSN*TTC were significantly associated with psoriasis, whereas recombinants retaining CDSN*TTC but lacking HLA-Cw6 were not associated, despite good statistical power. By grouping recombinants with similar breakpoints, the most telomeric quarter of the 298-kb candidate interval could be excluded with high confidence. These results strongly suggest that HLA-Cw6 is the PSORS1 risk allele that confers susceptibility to early-onset psoriasis.

Adult↗
PubMed2006

Microdermabrasion with and without aluminum oxide crystal abrasion: a comparative molecular analysis of dermal remodeling.

BACKGROUND: Microdermabrasion is a popular method of superficial skin resurfacing with effects on dermal remodeling. OBJECTIVE: The purpose of this study was to evaluate the relative importance of the two components of microdermabrasion, negative pressure and abrasion, in stimulating expression of key genes involved in dermal remodeling. METHODS: Ten subjects were treated with a microdermabrasion machine using focal crystal abrasion and negative pressure or negative pressure alone for 3 seconds. Serial biochemical analyses were performed. Reverse transcriptase real-time polymerase chain reaction assays were used to evaluate changes in transcription factor activator protein-1, primary cytokines (interleukin 1beta, tumor necrosis factor-alpha), and matrix metalloproteinases (MMP-1, MMP-3, MMP-9). RESULTS: Significant increases in gene expression of the c-Jun component of activator protein-1, interleukin 1beta, tumor necrosis factor-alpha, MMP-1, MMP-3, and MMP-9 were found with crystal abrasion combined with negative pressure. Negative pressure alone resulted in increased gene expression of MMP-1 and MMP-3 but of a quantitatively reduced magnitude when compared with negative pressure with crystal abrasion. LIMITATIONS: It is unclear that molecular changes seen with these treatments can result in clinical effect. CONCLUSION: The abrasive component of microdermabrasion is necessary for stimulating expression of key genes involved in dermal remodeling.

Adult↗
PubMed2006

CARD15 mutations in patients with plaque-type psoriasis and psoriatic arthritis: lack of association.

Psoriasis has a strong genetic component in the development of the disease as indicated by familial occurrence and a high concordance rate among monozygotic twins. In genome-wide scans for psoriasis several susceptibility loci have been detected, but the disease-causing genes have not yet been identified. A recent scan, performed on psoriatic arthritis (PsA), which occurs in about 15% of the psoriasis patients showed a significant locus on chromosome 16 in a region that was already described by genome scan for psoriasis. CARD15, a major susceptibility gene for Crohn's disease (CD) on chromosome 16q, is an interesting candidate gene for psoriasis, because there is a documented clinical association of CD with psoriasis, and recently the association of CARD15 mutations with PsA was reported in Newfoundland population. We investigated the association of this variant with PsA and the overall psoriasis genotype in 59 independent patients with PsA in comparison with 361 age and sex-matched controls. In addition, a second cohort of 89 independent North American PsA patients was included. The diagnosis of psoriasis was made by a dermatologist based on standard clinical criteria. In these patients, PsA was defined as an inflammatory joint disease, negative rheumatoid factor, and lack of another causative condition for arthritis. Using case-control analysis, the G908R mutation was weakly associated with psoriasis and PsA, but due to the low frequency of this mutation statistical significance was not reached. All other variants including leu1007fsinsC and R702W did not show any association with psoriasis or PsA. In conclusion, a disease-causing role for CARD15 mutations could not be confirmed in German or American subjects with PsA.

Arthritis, Psoriatic↗
PubMed2006

Retinoid-induced epidermal hyperplasia is mediated by epidermal growth factor receptor activation via specific induction of its ligands heparin-binding EGF and amphiregulin in human skin in vivo.

Retinoids are widely used in the treatment of photoaging to stimulate dermal repair. However, retinoids also induce epidermal hyperplasia, which can lead to excessive scaling. Scaling is the major deterrent to topical retinoid therapy. Keratinocyte growth is strongly stimulated via ligand activation of EGFR. We examined regulation of EGFR ligands by retinoids and the role of EGFR in retinoid-induced hyperplasia in human skin in vivo. Topical treatment of human skin with all-trans retinoic acid (tRA) induces EGFR ligands heparin-binding (HB)-EGF and amphiregulin (AR), and reduces betacellulin mRNA levels. Laser capture microdissection-coupled real-time reverse transcription-PCR reveals that tRA increases HB-EGF mRNA throughout the epidermis, whereas AR induction is limited to basal keratinocytes. Topical tRA activates extracellular signal-regulated kinase 1/2 (Erk1/2) downstream EGFR effectors in human skin in vivo. tRA increases the soluble forms of AR and HB-EGF proteins, and induces epidermal hyperplasia, in human skin organ culture. Neutralization of HB-EGF or AR with specific antibodies strongly reduces tRA-induced epidermal hyperplasia. Finally, inhibition of EGFR activation by genistein reduces epidermal hyperplasia caused by topical retinoid treatment. These data demonstrate the central role of EGFR activation in retinoid-induced epidermal hyperplasia, and suggest that EGFR inhibitors can mitigate retinoid-induced scaling.

Amphiregulin↗
PubMed2006

Epidermal growth factor receptor is a critical mediator of ultraviolet B irradiation-induced signal transduction in immortalized human keratinocyte HaCaT cells.

Epidermal growth factor receptor (EGFR) is a critical mediator of several types of epithelial cancers. Skin cancer arising from exposure to ultraviolet B irradiation (UVB) from the sun is a prominent form of human cancer. Recent data indicate that in addition to cognate ligands, EGFR is activated by UVB irradiation. We used pharmacological and genetic approaches to investigate the function of EGFR in mediating UVB-induced signal transduction in human skin keratinocyte HaCaT cells. Pharmacological inhibition of EGFR tyrosine kinase significantly inhibited UVB-mediated induction of ERK, p38, and JNK MAP kinases, and their effectors, transcription factors c-Fos and c-Jun. Inhibition of UVB activation of EGFR also suppressed activation of AKT-, PKC-, and PKA-dependent signal transduction pathways. B82 mouse L cells devoid of EGFR were used to further investigate EGFR dependence of UVB-induced signal transduction. UVB failed to induce ERK, and JNK activation was reduced 60% in B82 cells compared to B82K+ cells, which express EGFR. In addition, UVB induced both c-Fos and c-Jun proteins in B82K+ cells, whereas neither were induced in B82 cells. Taken together, these data demonstrate that EGFR is required for UVB-mediated induction of multiple signaling pathways that are known to mediate tumor formation in skin.

Animals↗
PubMed2006

Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation.

Reduced synthesis of collagen types I and III is characteristic of chronologically aged skin. The present report provides evidence that both cellular fibroblast aging and defective mechanical stimulation in the aged tissue contribute to reduced collagen synthesis. The reduction in collagen synthesis due to fibroblast aging was demonstrated by a lower in vitro production of type I procollagen by dermal fibroblasts isolated from skin of young (18 to 29 years) versus old (80+ years) individuals (82 +/- 16 versus 56 +/- 8 ng/ml; P < 0.05). A reduction in mechanical stimulation in chronologically aged skin was inferred from morphological, ultrastructural, and fluorescence microscopic studies. These studies, comparing dermal sections from young and old individuals, demonstrated a greater percentage of the cell surface attached to collagen fibers (78 +/- 6 versus 58 +/- 8%; P < 0.01) and more extensive cell spreading (1.0 +/- 0.3 vs. 0.5 +/- 0.3; P < 0.05) in young skin compared with old skin. These features are consistent with a lower level of mechanical stimulation on the cells in old versus young skin. Based on the findings presented here, we conclude that reduced collagen synthesis in chronologically aged skin reflects at least two different underlying mechanisms: cellular fibroblast aging and a lower level of mechanical stimulation.

Adolescent↗
PubMed2006

Elevated cysteine-rich 61 mediates aberrant collagen homeostasis in chronologically aged and photoaged human skin.

Alterations of human skin connective tissue structure and function are prominent features of chronological aging and solar UV irradiation-induced premature aging (photoaging). These skin connective tissue abnormalities result, in part, from reduced synthesis and elevated degradation of type I collagen, the major structural protein in skin. Here, we report that cysteine-rich 61 (CYR61/CCN1), a novel mediator of collagen homeostasis, is predominantly expressed in human skin connective tissue and is significantly elevated in fibroblasts in chronologically aged (80+ years) and photoaged human skin in vivo. In cultured human skin fibroblasts, elevated CYR61 expression substantially reduces type I procollagen and concurrently increases matrix metalloproteinase-1 (MMP-1), which initiates fibrillar collagen degradation. Elevated CYR61 caused down-regulation of transforming growth factor-beta type II receptor mRNA and protein levels, thereby impairing the transforming growth factor-beta pathway, which reduced type I procollagen and raised MMP-1 expression. Furthermore, elevated CYR61 induced transcription factor activator protein-1 (AP-1), which functions to stimulate MMP-1 expression. Thus, elevated expression of CYR61 in human skin fibroblasts acts through multiple pathways to cause alterations of collagen homeostasis similar to those pathways observed in aged human skin in vivo. These data identify CYR61 as a pivotal regulator of collagen production and degradation in aged and photoaged human skin.

Adult↗
PubMed2005

Receptor-type protein-tyrosine phosphatase-kappa regulates epidermal growth factor receptor function.

Epidermal growth factor receptor (EGFR), the prototypic receptor protein tyrosine kinase, is a major regulator of growth and survival for many epithelial cell types. We report here that receptor-type protein-tyrosine phosphatase-kappa (RPTP-kappa) dephosphorylates EGFR and thereby regulates its function in human keratinocytes. Protein-tyrosine phosphatase (PTP) inhibitors induced EGFR tyrosine phosphorylation in intact primary human keratinocytes and cell-free membrane preparations. Five highly expressed RPTPs (RPTP-beta, delta, kappa, mu, and xi) were functionally analyzed in a Chinese hamster ovary (CHO) cell-based expression system. Full-length human EGFR expressed in CHO cells, which lack endogenous EGFR, displayed high basal (i.e. in the absence of ligand) tyrosine phosphorylation. Co-expression of RPTP-kappa, but not other RPTPs, specifically reduced basal EGFR tyrosine phosphorylation. RPTP-kappa also reduced epidermal growth factor-dependent EGFR tyrosine phosphorylation in CHO cells. Purified RPTP-kappa preferentially dephosphorylated EGFR tyrosines 1068 and 1173 in vitro. Overexpression of wild-type or catalytically inactive RPTP-kappa reduced or enhanced, respectively, basal and EGF-induced EGFR tyrosine phosphorylation in human keratinocytes. Furthermore, siRNA-mediated knockdown of RPTP-kappa increased basal and EGF-stimulated EGFR tyrosine phosphorylation and augmented downstream Erk activation in human keratinocytes. RPTP-kappa levels increased in keratinocytes as cells reached confluency, and overexpression of RPTP-kappa in subconfluent keratinocytes reduced keratinocyte proliferation. Taken together, the above data indicate that RPTP-kappa is a key regulator of EGFR tyrosine phosphorylation and function in human keratinocytes.

Animals↗
PubMed2005

Dermal matrix remodeling after nonablative laser therapy.

OBJECTIVE: Nonablative laser therapy is widely practiced for cutaneous rejuvenation. We sought to quantify dermal molecular changes after exposure of photodamaged skin to nonablative laser energy. METHODS: Nonablative laser therapy of forearm skin using either a 585-nm wavelength pulsed dye laser or a 1320-nm wavelength neodymium:yttrium-aluminum-garnet laser was performed. Serial biopsy specimens were obtained at baseline and various times after treatment. RESULTS: Statistically significant increases in type I procollagen messenger RNA expression occurred after exposure of photodamaged skin to each laser. Induction was 47% (P < .05) and 84% (P < .05) above baseline levels 1 week after laser therapy among those treated with the pulsed dye and neodymium:yttrium-aluminum-garnet lasers, respectively. Substantial induction of type III procollagen, various matrix metalloproteinases, and primary cytokines was also demonstrated. Responses with respect to all molecules studied were highly variable. LIMITATIONS: This study addresses molecular changes after a single laser exposure whereas clinically, serial treatments are often provided. CONCLUSIONS: Nonablative laser therapy may result in quantifiable alterations in molecules associated with remodeling of the dermal matrix, although responses vary greatly among patients.

Aged↗
PubMed2005

Microdermabrasion: a molecular analysis following a single treatment.

BACKGROUND: Microdermabrasion is a popular method of superficial skin resurfacing. It is unclear if dermal remodeling actually occurs. OBJECTIVE: To rigorously investigate the molecular alterations observed following a single microdermabrasion treatment. METHODS: Forty-nine subjects received a single microdermabrasion treatment to buttock skin. Serial in vivo biochemical and immunohistological analyses were performed. Reverse transcriptase real-time polymerase chain reaction and immunohistochemistry assays were used to evaluate changes in transcription factors (AP-1, NF-kappaB), primary cytokines (interleukin-1beta, tumor necrosis factor-alpha), matrix metalloproteinases (MMP-1, MMP-3, MMP-9), barrier repair enzymes (acetyl-coenzyme A carboxylase, 3-hydroxy-3-methylglutaryl coenzyme A reductase), and type I procollagen. Results Elevation of transcription factors, primary cytokines, and matrix metalloproteinases occurs rapidly after a single microdermabrasion treatment. Two of 11 subjects also demonstrated increased type I procollagen messenger RNA and protein levels 14 days after treatment. No alteration in stratum corneum thickness was detected. CONCLUSION: Microdermabrasion activates a dermal remodeling/wound healing cascade with minimal epidermal disruption. Evidence now exists to further study manipulation of variables such as number and timing of microdermabrasion sessions.

Acetyl-CoA Carboxylase↗
PubMed2005

Long-term treatment of photoaged human skin with topical retinoic acid improves epidermal cell atypia and thickens the collagen band in papillary dermis.

BACKGROUND: Risk of photocarcinogenesis and the relevance of collagen in wrinkle effacement are two issues related to prolonged use of retinoic acid (RA) that have not been fully addressed. OBJECTIVE: Our purpose was to investigate the degree of epidermal cellular atypia and the thickness of papillary dermal collagen in photoaging after long-term use of RA. METHODS: Thirty-four subjects with photoaged skin were treated daily with 0.05% RA for at least 6 months. Epidermal cellular atypia was graded by means of a semiquantitative scale. Thickness of collagen band was measured by using image-analysis software. RESULTS: Compared with pretreatment findings, melanocytic and keratinocytic atypia was significantly reduced and the collagen band thickness doubled. LIMITATIONS: This was an open-label study. CONCLUSION: Improvement in epidermal cellular atypia is consistent with the ability of RA to act as a chemopreventive agent in epithelial carcinogenesis. Prolonged use also significantly increased collagen matrix deposition in dermal repair zones, which most likely contributes to wrinkle effacement by RA.

Administration, Topical↗
PubMed2005

Amphiregulin and epidermal hyperplasia: amphiregulin is required to maintain the psoriatic phenotype of human skin grafts on severe combined immunodeficient mice.

Overexpression of amphiregulin has been shown to induce psoriasiform changes in the skin of transgenic mice shortly after birth. Therefore, amphiregulin has been suggested as a target for anti-psoriatic therapy. To test this theory, a humanized monoclonal antibody capable of neutralizing human amphiregulin was examined for anti-proliferative effects in the human skin-severe combined immunodeficient (SCID) mouse transplant model. The anti-amphiregulin antibody reduced epidermal thickness of transplanted psoriatic skin and also inhibited the hyperplastic response that developed in nonpsoriatic skin after transplantation. The same antibody also suppressed keratinocyte proliferation in monolayer culture in a dose-dependent manner. Under the same conditions in which keratinocyte proliferation was inhibited, the antibody had little effect on proliferation of human dermal fibroblasts and no effect on type I procollagen production by these cells. Taken together, these data indicate an important role for amphiregulin in psoriatic hyperplasia and suggest that inhibition of amphiregulin activity could be an efficacious therapeutic strategy for psoriasis. These data also suggest that the hyperplastic response occurring in nonpsoriatic human skin on transplantation to the SCID mouse is mediated, in large part, by amphiregulin.

Amphiregulin↗
PubMed2005

Inflammation and extracellular matrix degradation mediated by activated transcription factors nuclear factor-kappaB and activator protein-1 in inflammatory acne lesions in vivo.

Acne is the most common skin disease, causing significant psychosocial problems for those afflicted. Currently available agents for acne treatment, such as oral antibiotics and isotretinoin (Accutane), have limited use. Thus, development of novel agents to treat this disease is needed. However, the pathophysiology of acne inflammation is poorly understood. Before new therapeutic strategies can be devised, knowledge regarding molecular mechanisms of acne inflammation is required. We report here that transcription factors nuclear factor-kappaB and activator protein-1 are activated in acne lesions with consequent elevated expression of their target gene products, inflammatory cytokines and matrix-degrading metalloproteinases, respectively. These elevated gene products are molecular mediators of inflammation and collagen degradation in acne lesions in vivo. This new knowledge enables a rational strategy for development of pharmacological agents that can target the inflammation and matrix remodeling that occurs in severe acne.

Acne Vulgaris↗
PubMed2004

Ultraviolet irradiation induces Smad7 via induction of transcription factor AP-1 in human skin fibroblasts.

Smad7 functions as an endogenous negative regulator of transforming growth factor-beta (TGF-beta)/SMAD signaling. The TGF-beta/SMAD pathway is a major regulator of collagen production in connective tissue. Reduced expression of SMAD7 has been reported in TGF-beta-mediated fibrotic diseases, characterized by overproduction of collagen. Solar ultraviolet (UV) irradiation reduces collagen production by fibroblasts in human skin in vivo. We have investigated regulation of Smad7 gene expression by UV irradiation in human skin fibroblasts. UV irradiation transiently increased SMAD7 mRNA and protein levels. Induction of SMAD7 mRNA and protein was maximal within 5 h and returned to initial basal levels 24 h post-UV irradiation. UV irradiation induced Smad7 promoter-reporter activity 3-fold. The Smad7 promoter contains functional enhancer sequences that bind transcription factors SMAD3 and activator protein-1 (AP-1). UV irradiation reduced protein binding to the Smad3 enhancer and increased binding to the AP-1 enhancer. Deletion of the AP-1 binding site in the Smad7 promoter completely abolished UV stimulation of SMAD7 transcription. Deletion of the Smad3 element had no effect on UV irradiation-induced promoter activity. UV irradiation increased mRNA and protein expression of the AP-1 family members, c-Jun and c-Fos, which bound to the AP-1 element in the Smad7 promoter. Furthermore, overexpression of dominant negative c-Jun substantially reduced UV irradiation induction of SMAD7 transcription. These data demonstrate that induction of Smad7 gene expression by UV irradiation is mediated via induction of the transcription factor AP-1 in human skin fibroblasts.

Base Sequence↗
PubMed2004

Treatment of acne vulgaris with a pulsed dye laser: a randomized controlled trial.

CONTEXT: The high prevalence of acne vulgaris and its significant morbidity underscore the need for convenient, low-risk, and efficacious therapy. Treatment with various lasers has been reported to improve acne. OBJECTIVE: To evaluate the clinical efficacy of pulsed dye laser therapy in the treatment of acne. DESIGN, SETTING, AND PATIENTS: Randomized, single-blind, controlled, split-face clinical trial of a volunteer sample of 40 patients aged 13 years or older with facial acne conducted at an academic referral center from August 2002 to September 2003. INTERVENTION: One or 2 nonpurpuric pulsed dye laser treatments to half of the face (fluence of 3 J/cm2), serial blinded clinical assessments (lesion counts), and grading of acne severity using standardized bilateral serial photographs. MAIN OUTCOME MEASURES: Comparison of the changes in lesion counts from baseline to 12 weeks between treated and untreated sides of the face and changes in photographic evidence of acne severity as graded by a panel of dermatologists blinded to treatment assignment. RESULTS: After 12 weeks, using intent-to-treat analysis with last observation carried forward, there were no significant differences between laser-treated and untreated skin for changes in mean papule counts (-4.2 vs -2.2; P =.08), mean pustule counts (0 vs -1.0; P =.12), or mean comedone counts (2.9 vs 1.6; P =.63). Grading of serial photographs confirmed the clinical assessments, showing no significant mean (SE) differences in Leeds scores (range, 1-12) for treated skin (3.98 [0.32] at baseline and 3.94 [0.27] at week 12) compared with untreated skin (3.83 [0.32] at baseline and 3.79 [0.28] at week 12) (P>.99). CONCLUSIONS: In this study, the nonpurpuric pulsed dye laser therapy did not result in significant improvement of facial acne. More research is needed before this laser therapy may be recommended as an acne treatment.

Acne Vulgaris↗