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Biomedical subjects

Jan C Simon

Publications and source records attributed to Jan C Simon.

At least 19 recordsLinked to original sources
PubMed2006

Differential regulation of hyaluronan metabolism in the epidermal and dermal compartments of human skin by UVB irradiation.

Hyaluronan (HA), a major component of the cutaneous extracellular-matrix, is involved in tissue repair. Human skin is exposed to and damaged by UVB-irradiation. Here, we investigate the regulation of HA metabolism in human skin during acute UVB-induced inflammation. Expression of HA synthesizing (HAS) and degrading enzymes hyaluronidase (HYAL) as evaluated by quantitative reverse transcribed PCR in response to UVB differed when fibroblasts and HaCaT-keratinocytes, representative cell types in dermis and epidermis, respectively, were compared. Both demonstrated temporally different expression patterns of these genes 3- and 24-hours post-irradiation. This resulted 24-hours post-irradiation in an increase in HAS gene expression in both fibroblasts and HaCaT-keratinocytes, and an increase in HYAL expression only in fibroblasts. HA-production as analyzed by the HA content of conditioned medium was reduced in HaCaT and fibroblast cultures 3-hours post-irradiation, whereas HA increased in HaCaT-cultures 24-hours post-irradiation but remained suppressed in fibroblasts-cultures. Consistently, immunohistochemical staining for HA in human skin 24-hours post-irradiation demonstrated an increased epidermal HA, but a decrease in the dermal compartment. Moreover, analysis of the HA content of dermal microdialysis-fluid revealed increased accumulation of HA degradation products 24-hours post-irradiation. These data demonstrate that there is a complex temporal and spatial regulation of HA-metabolism in skin in response to UVB irradiation.

Cells, Cultured↗
PubMed2006

Patient perspectives on the management of atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is increasingly common, with a point prevalence of more than 30% in some countries, and is characterized by visible skin lesions and intense itching. OBJECTIVE: The International Study of Life with Atopic Eczema (ISOLATE) is the first large-scale study to assess the effect of AD on the lives of patients and society, how patients and caregivers manage the condition, and how well patients and caregivers currently believe that AD is controlled. METHODS: Two thousand two patients (>13 years) and caregivers of children (2-13 years) with moderate-to-severe AD randomly selected from 8 countries underwent standardized telephone interviews using questions developed in collaboration with national eczema patient groups and physicians. RESULTS: During each year, patients spend, on average, 1 of 3 days in flare. The majority of patients receive prescription topical corticosteroids to treat flares; however, 49% of respondents are concerned about using these agents. On average, patients and caregivers delay initiating treatment for 7 days after onset of a flare. Only 24% of patients and caregivers feel confident they can manage AD flares adequately. Seventy-five percent of caregivers and patients feel that being able to effectively control AD would be the single most important improvement to their or their child's quality of life. The avoidable secondary economic cost of AD is estimated at 2 billion Euro per year across the European Union. CONCLUSION: ISOLATE highlights the need to improve patients' control of AD to reduce the significant effect this condition has on the patient and society. CLINICAL IMPLICATIONS: ISOLATE shows that patients with AD are untreated for half the time they are in flare, and thus there is an urgent need for physicians to ensure that the patients are educated and confident in using medication as prescribed to gain disease control.

Adolescent↗
PubMed2006

The signal-to-noise ratio as a measure of HA oligomer concentration: a MALDI-TOF MS study.

MALDI-TOF MS (matrix-assisted laser desorption and ionization time-of-flight mass spectrometry) was used to determine ng amounts of defined hyaluronan (HA) oligomers obtained by enzymatic digestion of high molecular weight HA with testicular hyaluronate lyase. The signal-to-noise (S/N) ratio of the positive and negative ion spectra represents a reliable concentration measure: Amounts of HA down to about 40 fmol could be determined and there is a linear correlation between the S/N ratio and the HA amount between about 0.8 pmol and 40 fmol. However, the detection limits depend considerably on the size of the HA oligomer with larger oligomers being less sensitively detectable. The advantages and drawbacks of the S/N ratio as concentration measure are discussed.

Animals↗
PubMed2006

Increased neutrophil adherence in psoriasis: role of the human endothelial cell receptor Thy-1 (CD90).

The chronic inflammatory skin disease psoriasis is characterized by prominent skin infiltration by neutrophils and microabscess formation. The adhesion of leukocytes and subsequent transmigration through the activated endothelium is one prerequisite for the accumulation of these cells in skin. In recent studies, the human Thy-1 (CD90) was characterized as an adhesion molecule on activated endothelial cells (ECs) mediating the adhesion of neutrophils via the interaction with the beta2-integrin Mac-1. Based on these novel findings, we compared the roles of Thy-1 and ICAM-1 in the adhesion of neutrophils from patients with psoriasis to activated ECs. The adhesion of peripheral blood neutrophils of patients suffering from psoriasis to Thy-1-transfected cells as well as to activated, Thy-1-expressing human dermal microvascular ECs (HDMECs) is distinctly increased in comparison to the adhesion of neutrophils from healthy controls. In contrast, adherence of psoriatic neutrophils to ICAM-1 transfectants is, if at all, only slightly enhanced compared to healthy controls. The interaction of healthy as well as psoriatic polymorphonuclear cells to Thy-1 transfectants and HDMECs was significantly inhibited by blocking Thy-1 on ECs or its receptor Mac-1 on neutrophils, indicating the importance of this interaction for the adhesion of neutrophils to activated endothelium. In conclusion, our data indicate that the adhesion of neutrophils to activated ECs mediated by Thy-1/Mac-1 interaction is an important attachment mechanism facilitating their subsequent migration into lesional psoriatic skin.

Adult↗
PubMed2006

Solar simulator-induced phototoxicity of the furoquinoline alkaloid dictamnine compared to 8-methoxypsoralen and 5-methoxypsoralen.

Dictamnine, a furoquinoline alkaloid of the Rutaceae plant family, has been shown to be mutagenic and phototoxic in bacteria and yeasts. Here, we have investigated the phototoxic effect of dictamnine in human Jurkat T cells and HaCaT keratinocytes. Dictamnine was isolated from the roots of DICTAMNUS ALBA L. and was photoactivated with solar simulated radiation, delivered from a 1000-W xenon arc lamp with a maximal output between 300 - 800 nm. Dictamnine displayed concentration- and light-dependent phototoxic effects in both cell lines. In comparison to the structurally related furocoumarins 5-methoxypsoralen and 8-methoxypsoralen, dictamnine was less phototoxic. Nevertheless, it may play a major role in the elicitation of phytophotodermatitis because of its abundance in plants of the Rutaceae family.

5-Methoxypsoralen↗
PubMed2006

In situ profiling and quantification of cytokines released during ultraviolet B-induced inflammation by combining dermal microdialysis and protein microarrays.

In skin, an evolving inflammatory or immune response is triggered by early release of a cytokine cascade into the extracellular space. Investigation of extracellular cytokine secretion in situ has been limited by low cut-off filtering membranes and sample volume size and the inability to monitor changes in cytokine protein levels in real-time in situ. Here, we combine for the first time the methods of intradermal microdialysis and antibody protein arraying to profile the early cascade of multiple cytokines in a complex inflammatory response exemplified by ultraviolet B (UVB)-induced inflammation. We observed significant differences of the cytokine and growth factor responses after tissue injury by catheter placement and UVB-induced inflammation. UVB irradiation initiates a rapid proinflammatory response followed by a mixed TH1/TH2 response in which ultimately TH2 cytokines IL-4 and IL10 predominated after 24 h. This most likely indicates the termination and self limitation of the inflammatory response. We conclude that the combination of dermal microdialysis and protein microarray offers a powerful tool to analyze in real-time the complex and rapidly changing interstitial protein milieu during cutaneous inflammatory responses.

Adult↗
PubMed2006

[Vacuum therapy in dermatology: a review].

Modern wound therapy is developing continuously. Vacuum therapy is an established procedure to treat wounds. Available on the market is, among others, the V.A.C. (Vacuum Assisted Closure) therapy system. Here, we report the various effects of the vacuum therapy on wounds such as reducing the bacterial contamination, improving granulation and microcirculation and focus on the practical use of the V.A.C., possible complications, contraindications and the economic aspects of the therapy. Since V.A.C. therapy allows rapid mobilization of patients especially with postoperative or posttraumatic wounds, infrequent dressing changes and relative analgesia, this treatment modality is well-accepted by patients with acute or chronic wounds. One explanation for the high acceptance on part of the therapists and the widespread use of the method are the excellent clinical results.

Equipment Design↗
PubMed2005

Interaction of human Thy-1 (CD 90) with the integrin alphavbeta3 (CD51/CD61): an important mechanism mediating melanoma cell adhesion to activated endothelium.

The expression of the alphavbeta3 integrin (CD51/CD61) on human melanoma cells has been shown to be associated most closely with tumor progression and metastases formation in melanoma. Here, we demonstrated a specific interaction of the alphavbeta3 integrin on melanoma cells with the human Thy-1, an inducible cell adhesion molecule expressed on the cell surface of activated endothelial cells (EC). The interaction was shown by the binding of purified Thy-1 protein to alpha(V)beta(3) transfected cells, to alphavbeta3-expressing melanoma cells and to purified alpha(V)beta(3) integrin. Moreover, melanoma cells adhere specifically to Thy-1 transfectants via alphavbeta3 on melanoma cells showing the functional relevance of this interaction for cell adhesion. Finally, the importance of the alphavbeta3/Thy-1 interaction for the adhesion of melanoma cells to the activated endothelium was confirmed under static and flow conditions by the inhibition of melanoma cell adhesion to and transmigration across activated EC by blocking the alphavbeta3/Thy-1 interaction. In conclusion, we have identified a new pair of adhesion molecules Thy-1 and alphavbeta3 mediating the interaction of melanoma cells and activated EC. These data explain at least in part the high tumorigenicity of alphavbeta3-expressing melanoma cells and the association of alphavbeta3-positive melanoma cells with a high risk of metastasis and poor prognosis.

Cell Adhesion↗
PubMed2005

Osteopontin functionally activates dendritic cells and induces their differentiation toward a Th1-polarizing phenotype.

Osteopontin (OPN) has been shown to have T helper 1 (Th1) cytokine functions in cell-mediated immunity. Deficiency of OPN is linked to a reduced Th1 immune response in autoimmunity, infectious disease, and delayed-type allergy. Dendritic cells (DCs) are central for the induction of T-cell-mediated immunity, when initially flexible DCs are instructed by priming signals and tissue-derived factors to adopt Th1, Th2, or regulatory T-cell-inducing phenotypes. Although OPN influences the cytokine secretion of T cells and macrophages, its effects on DC polarization remain an important missing link in the understanding of OPN functions in Th1 immunity. Here we demonstrate that OPN promotes the emigration of human DCs from the epidermis and functionally activates myeloid-type DCs, augmenting their expression of HLA-DR, costimulatory, and adhesion molecules. OPN induces their Th1-promoting tumor necrosis factor alpha (TNF-alpha) and interleukin-12 (IL-12) secretion, and enhances their allostimulatory capacity. In mixed lymphocyte reactions (MLRs), OPN stimulates IL-12 secretion by DCs, inducing elevated interferon-gamma (IFN-gamma) production by T cells. Naive Th cells stimulated by OPN-activated DCs show a Th1-polarized cytokine production. Our findings identify OPN as an important tissue-derived factor that DCs encounter when traveling from peripheral sites of activation to secondary lymphatic organs, which induces DC maturation toward a Th1-promoting phenotype.

Cell Differentiation↗
PubMed2005

Aristoforin, a novel stable derivative of hyperforin, is a potent anticancer agent.

Hyperforin, a natural product of St. John's wort (Hypericum perforatum L.), has a number of pharmacological activities, including antidepressive and antibacterial properties. Furthermore, hyperforin has pronounced antitumor properties against different tumor cell lines, both in vitro and in vivo. Despite being a promising novel anticancer agent, the poor solubility and stability of hyperforin in aqueous solution limits its potential clinical application. In this study, we present the synthesis of hyperforin derivatives with improved pharmacological activity. The synthesized compounds were tested for their solubility and stability properties. They were also investigated for their antitumor properties, both in vitro and in vivo. One of these hyperforin derivatives, Aristoforin, is more soluble in aqueous solution than hyperforin and is additionally highly stable. Importantly, it retains the antitumor properties of the parental compound without inducing toxicity in experimental animals. These data strongly suggest that Aristoforin has potential as an anticancer drug.

Animals↗
PubMed2005

Hyperforin acts as an angiogenesis inhibitor.

Hyperforin is a plant compound from Hypericum perforatum that inhibits tumor cell proliferation in vitro by induction of apoptosis. Here, we report that hyperforin also acts as an angiogenesis inhibitor in vitro and in vivo. In vitro, hyperforin blocked microvessel formation of human dermal microvascular endothelial cells (HDMEC) on a complex extracellular matrix. Furthermore, hyperforin reduced proliferation of HDMEC in a dose-dependent manner, without displaying toxic effects or inducing apoptosis of the cells. To evaluate the antiangiogenic activity of hyperforin in vivo, Wistar rats were subcutaneously injected with MT-450 mammary carcinoma cells and were treated with peritumoral injections of hyperforin or solvent. Hyperforin significantly inhibited tumor growth, induced apoptosis of tumor cells and reduced tumor vascularization, as shown by in situ staining of CD31-positive microvessels in the tumor stroma. These data suggest that, in addition to the induction of tumor cell apoptosis, hyperforin can also suppress angiogenesis by a direct, non-toxic effect on endothelial cells.

Angiogenesis Inhibitors↗
PubMed2005

MEL4B3, a novel mRNA is induced in skin tumors and regulated by TGF-beta and pro-inflammatory cytokines.

Tumor-stroma interactions play a decisive role in the growth and metastasis of solid tumors, and involve signalling either by soluble mediators or direct cell-cell interaction. Here, we report the isolation and characterisation of a novel cDNA (MEL4B3), which is induced in cultured dermal fibroblasts exposed to supernatants of melanoma cell lines. MEL4B3 shares high homology with two predicted cDNA sequences for which no activity has so far been described. In situ hybridisation revealed the expression of MEL4B3 in malignant melanoma increasing with tumor depth; in basal cell carcinoma and in squamous cell carcinoma. MEL4B3 was barely detectable in normal skin or non-malignant melanocytic naevi. Furthermore, MEL4B3 was expressed at high level in the epidermis of psoriatic skin. In vitro, the expression of MEL4B3 was found to be induced by the exposure of human dermal fibroblasts to melanoma cell culture supernatants or to transforming growth factor-beta, interleukin-1 and tumor necrosis factor-alpha. The expression MEL4B3 therefore reflects closely cell activation occurring during tumor growth, metastasis and inflammation.

Amino Acid Sequence↗
PubMed2005

[Anaphylactic reaction to soy drink in three patients with birch pollen allergy].

Three patients presented with anaphylactic reactions to soy drink. Cross-reactivity of soy protein with birch pollen allergens was identified as the cause for their severe reactions. Because of the rising popularity of soy products and the large number of birch pollen allergic patients, allergologists will be increasingly confronted with these reactions in future. Patients with birch pollen allergy should avoid the intake of soy protein.

Anaphylaxis↗
PubMed2004

Fas-mediated inhibition of CD4+ T cell priming results in dominance of type 1 CD8+ T cells in the immune response to the contact sensitizer trinitrophenyl.

One of the unusual properties of chemically reactive haptens is their capacity to simultaneously generate immunogenic determinants for hapten-specific CD8(+) and CD4(+) T cells. Surprisingly, however, a clear dominance of CD8(+) effector T cells is observed in murine contact hypersensitivity to various haptens and upon T cell priming with hapten-modified APCs in vitro. In this study we show that trinitrophenyl-specific CD8(+) T cells actively prevent CD4(+) T cell priming in vitro. This process requires cell-cell contact and is dependent on the expression of Fas on the CD4(+) T cells. Our results reveal an important Fas-dependent mechanism for the regulation of hapten-specific CD4(+) T cell responses by CD8(+) T cells, which causes the dominance of CD8(+) effector T cells and the active suppression of a CD4(+) T cell response. Moreover, our demonstration of reduced contact hypersensitivity to trinitrophenyl in the absence of Fas, but not of perforin and/or granzymes A and B, underlines the important role of Fas as a pathogenetic factor for contact hypersensitivity.

Animals↗
PubMed2004

Hyaluronan fragments stimulate endothelial recognition of injury through TLR4.

Tissues must quickly recognize injury to respond to the rapid pace of microbial growth. In skin, dermal microvascular endothelial cells must also react to danger signals from the surrounding tissue and immediately participate by initiating the wound repair process. Components of the extracellular matrix such as hyaluronan are rapidly broken down into smaller molecular weight oligosaccharides in a wound, and these can activate a variety of biological processes. This study set out to determine if hyaluronan fragments released following injury can stimulate endothelial cells and what mechanism is responsible for this response. Using genechip microarray analysis, a response to hyaluronan fragments was detected in endothelial cells with the most significant increase observed for the chemokine IL-8. This observation was verified with qualitative reverse transcriptase-PCR and ELISA in human endothelial cell culture, and in a mouse model by observing serum levels of MIP-2 and KC following hyaluronan fragment administration in vivo. Activation was TLR4-dependent, as shown by use of TLR4 blocking antibody and TLR4-deficient mice, but not due to the presence of undetected contaminants as shown by inactivation following digestion with the hyaluronan-degrading enzyme chondroitinase ABC or incubation with the hyaluronan-specific blocking peptide Pep-1. Inactivation of LPS activity failed to diminish the action of hyaluronan fragments. These observations suggest that endogenous components of the extracellular matrix can stimulate endothelia to trigger recognition of injury in the initial stages of the wound defense and repair response.

Animals↗